Heterobicyclic compounds useful as kinase inhibitors

ABSTRACT

A compound of Formula (I) 
     
       
         
         
             
             
         
       
     
     and enantiomers, diastereomers and pharmaceutically-acceptable salts thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula I, and methods of treating conditions associated with the activity of p38 kinase.

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/861,168 filed Nov. 27, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

This invention relates to heterobicyclic compounds useful for treatingkinase-associated conditions, such as p38 kinase-associated conditions.The invention further pertains to pharmaceutical compositions containingat least one compound according to the invention useful for treatingkinase-associated conditions, such as p38 kinase-associated conditions,and methods of inhibiting the activity of kinase in a mammal.

BACKGROUND OF THE INVENTION

A large number of cytokines participate in the inflammatory response,including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines suchas IL-1 and TNF-α are implicated in a wide variety of diseases,including inflammatory bowel disease, rheumatoid arthritis, psoriasis,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,and congestive heart failure, among others [Henry et al., Drugs Fut.,24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823(1999)]. Evidence in human patients indicates that protein antagonistsof cytokines are effective in treating chronic inflammatory diseases,such as, for example, monoclonal antibody to TNF-α (Enbrel) [Rankin etal., Br. J. Rheumatol., 34:334-342 (1995)], and soluble TNF-αreceptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern.Med., 130:478-486 (1999)].

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as, for example, a mitogen, an infectiousorganism, or trauma. Important mediators of TNF-α production are themitogen-activated protein (MAP) kinases, and in particular, p38 kinase.These kinases are activated in response to various stress stimuli,including, but not limited to, proinflammatory cytokines, endotoxin,ultraviolet light, and osmotic shock.

One important MAP kinase is p38 kinase, also known as cytokinesuppressive anti-inflammatory drug binding protein (CSBP) or IK.Activation of p38 requires dual phosphorylation by upstream MAP kinasekinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyrmotif characteristic of p38 isozymes. There are four known isoforms ofp38, i.e., p38α, p38β, p38γ, and p38δ. The α and β isoforms areexpressed in inflammatory cells and are key mediators of TNF-αproduction. Inhibiting the p38α and β enzymes in cells results inreduced levels of TNF-α expression. Also, administering p38α and βinhibitors in animal models of inflammatory disease has proven that suchinhibitors are effective in treating those diseases. Accordingly, thep38 enzymes serve an important role in inflammatory processes mediatedby IL-1 and TNF-α.

Compounds that reportedly inhibit p38 kinase and cytokines, such as IL-1and TNF-α for use in treating inflammatory diseases, are disclosed inU.S. Pat. Nos. 6,277,989 and 6,130,235 to Scios, Inc; 6,147,080 and5,945,418 to Vertex Pharmaceuticals, Inc.; 6,251,914, 5,977,103 and5,658,903 to Smith-Kline Beecham Corp.; 5,932,576 and 6,087,496 to G. D.Searle & Co.; PCT Publication Numbers WO 00/56738 and WO 01/27089 toAstra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazolinederivatives as p38 kinase inhibitors); WO 00/56738 (pyridine andpyrimidine derivatives for the same purpose); WO 00/12497 (discusses therelationship between p38 kinase inhibitors); and WO 00/12074 (piperazineand piperidine compounds useful as p38 inhibitors).

The present invention provides certain heterobicyclic compounds usefulas kinase inhibitors, particularly kinases p38α and β. Each of thepatent applications, patents, and publications referred to herein isincorporated herein by reference as to the subject matter referenced.

SUMMARY OF THE INVENTION

The instant invention generally pertains to compounds of Formula (I),

and enantiomers, diastereomers and pharmaceutically-acceptable saltsthereof, wherein:

L and M are each independently selected from —N— and —C═ wherein both Land M cannot be —N— at the same time;

Q is selected from the group consisting of —N—, —C═, and a bond,wherein:

(a) Q is a bond when L is —N— and M is —C═;

(b) Q is a bond when L is —C═ and M is —N—; and

(c) Q is —N═ or —C═ when L and M are both —C═;

R¹ and R² are each independently selected at each occurrence from thegroup consisting of hydroxyl, halo, haloalkyl, optionally substitutedamino, optionally substituted alkoxy, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted heterocyclo,optionally substituted benzyl, optionally substituted benzoyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbamoyl and —[C(O)]₂NR⁷R⁸, wherein each of R⁷and R⁸ is independently an optionally substituted C₁₋₆ alkyl, andfurther wherein R⁷ and R⁸ can be taken together with the atoms to whichthey are attached to form an optionally substituted 5-6 member ring;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, hydroxyl, halo, haloalkyl, optionally substituted amino,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclo, optionally substituted benzyl, optionallysubstituted benzoyl, optionally substituted aryl, and optionallysubstituted heteroaryl; CO₂R¹¹, CONR¹¹R¹² and NR¹¹R¹², wherein each ofR¹¹ and R¹² are independently selected from the group consisting of H,C1-C6 straight or branched chain alkyl, C1-C4 straight or branched chainalkyl amino, C1-C4 straight or branched chain dialkyl amino, C1-C4straight or branched chain alkyl with an OH group, and C4-C10heterocyclo with 1-3 members selected from the group consisting of N, Sand O; provided there are no O—O or S—S bonds in R³ and R⁴ and any ofthe heterocyclo groups can be optionally substituted with a member ofthe group consisting of C1-C4 alkyl, optionally substituted amino, andalkyl amino;

ring A is aryl or heteroaryl;

B is —(CR⁵R⁶)_(q)— wherein R⁵ and R⁶ are each independently selectedfrom the group consisting of hydrogen and optionally substituted alkyl;

m is 0-2, wherein when m=2 (so that there are 2 R¹ groups (which may bethe same or different) off the phenyl ring, then (a) the 2 R¹ groups canbe separate substituents or (b) the 2 R¹ groups, together with thecarbons to which they are attached can form a fused ring, wherein (a)and (b) can each optionally be substituted with a member selected fromthe group consisting of cycloalkyl, benzyl, benzoyl, aryl, heterocycloand heteroaryl; and

n and q are each independently 0-3, more particularly 0-2.

More particular values for the groups are as follows:

R¹ is selected from the group consisting of hydrogen, halo, C1-C6 alkyl,cyano and haloalkyl, wherein the haloalkyls have 1-3 carbons and 1-5halogens (for example, CF₃, CH₂CF₃, and CF₂CH₃);

R² is selected from the group consisting of hydrogen; hydroxyl; halo;haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens (forexample, CF₃, CH₂CF₃, and CF₂CH₃); C1-C6 alkoxy; cyano; optionallysubstituted C1-C4 alkyl; C3-C6 cycloalkyl; heterocyclo (for example,having 4-12 carbon atoms and 1-5 members selected from the groupconsisting of nitrogen, oxygen, sulfur, provided that no O—O or S—Sbonds are present in the ring); aryl selected from phenyl and naphthyl;heteroaryl selected from pyridyl, thiophene, thiazole, indole, indazole,azaindole, quinoline, thiazole, benzthiazole, benzofuran andbenzimidazole; and

—[C(O)]₂NR⁷R⁸, wherein each of R⁷ and R⁸ is independently selected to beH or an optionally substituted C₁₋₆ alkyl, or R⁷ and R⁸ can be takentogether (with the carbons to which they are attached) to form anoptionally substituted (for example, C1-C4 alkyl or hydroxyl) 5-6membered ring;

R³ is selected from the group consisting of hydrogen and C1-C3 alkyl;

R⁴ is selected from the group consisting of hydrogen; hydroxyl; halo;haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens (forexample, CF₃, CH₂CF₃, and CF₂CH₃); CO₂R¹¹CONR¹¹R¹² or NR¹¹R¹² whereineach of R¹¹ and R¹² are independently selected from the group consistingof H, C1-C6 straight or branched chain alkyl, C1-C4 straight or branchedchain alkyl amino, C1-C4 straight or branched chain dialkyl amino, C1-C4straight or branched chain alkyl with an OH group, C4-C10 heterocyclowith 1-3 members selected from the group consisting of N, S and O,provided there is no O—O or S—S bonds in the ring and the heterocyclogroup can be optionally substituted with C1-C4 alkyl optionallysubstituted amino and alkyl amino;

B is —(CR⁵R⁶)_(q)— wherein R⁵ and R⁶ are each independently selectedfrom the group consisting of H and optionally substituted C1-C4 alkyl,wherein the substitutions are selected from the group consisting of, forexample, H and CH₃; ring A is a aryl or heteroaryl selected from thegroup consisting of phenyl, naphthyl, pyridyl, thiophene, indole,indazole, azaindole, quinoline, thiazole, benzthiazole, benzofuran andbenzimidazole;

m is 0-2;

n is 0-2; and

q is 0-2.

The invention further pertains to pharmaceutical compositions containingcompounds of Formula (I), and to methods of treating conditionsassociated with the activity of kinase, such as p38 (α and β),comprising administering to a mammal a pharmaceutically-acceptableamount of a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The terms “alkyl” and “alk” refers to a straight or branched chainalkane (hydrocarbon) radical containing from 1 to 12 carbon atoms,preferably 1 to 6 carbon atoms. Exemplary groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.

“Substituted alkyl” refers to an alkyl group substituted with one ormore substituents, preferably 1 to 4 substituents, at any availablepoint of attachment on the alkyl straight or branched chain. Exemplarysubstituents include one or more of the following groups: halo (e.g. asingle halo substituent or multiple halo substituents forming, in thelatter case, groups such as a perfluoroalkyl group or an alkyl groupbearing Cl₃ or CF₃), nitro, cyano, hydroxy, alkoxy, haloalkoxy (e.g.,trifluoromethoxy), —O-aryl, —O-heterocyclo, —O-alkylene-aryl,—O-haloalkyl, alkylthio, carboxy (i.e., —COOH), alkoxycarbonyl,alkylcarbonyloxy, carbamoyl, substituted carbamoyl, carbamate,substituted carbamate, urea, substituted urea, amidinyl, substitutedamidinyl, aryl, heterocycle, cycloalkyl, —NR^(c)R^(d),—OC(═O)NR^(c)R^(d), —C(═O)NR^(c)R^(d), —NR^(e)C(═O)NR^(c)R^(d),—NR^(e)C(O)²—NR^(c)R^(d), —N(R^(e))S(O)₂NR^(c)R^(d),—N(R^(e))P(O)₂NR^(c)R^(d), (wherein each of R^(c) and R^(d) isindependently selected from hydrogen, alkyl, aryl, and heterocyclo, andR^(e) is hydrogen, alkyl, or phenyl); and —SR^(f), —S(═O)R^(g),—S(O)₂R^(g), —NR^(e)S(O)₂—R^(g), —P(O)₂—R^(g), —NR^(e)C(═O)R^(f),—NR^(e)C(O)₂R^(f), —OC(═O)R^(f), —OC(═O)OR^(f), —C(═O)OR^(f) or—C(═O)R^(f) (wherein R^(e) is defined as immediately above, R^(f) ishydrogen, alkyl, aryl or heterocyclo, and R^(g) is alkyl, aryl, orheterocyclo). In the aforementioned substituents, in each instance, thealkyl, aryl, heterocyclo or cycloalkyl groups (R^(c), R^(d), R^(e),R^(f), and R^(g)) in turn can be optionally substituted with one tofour, preferably one to three further groups, selected from R^(k),—O—R^(k), cyano, nitro, haloalkyl, haloalkoxy, halo, —NR^(k)R^(m),—OC(═O)NR^(k)R^(m), —C(═O)NR^(k)R^(m), —NR^(k)C(═O)R^(m), —SR^(k),—S(═O)R^(n), —S(O)₂R^(n), —OC(═O)R^(k), —C(═O)OR^(k), —C(═O)R^(k),phenyl, benzyl, phenyloxy, or benzyloxy, or a lower alkyl substitutedwith one to two of —O—R^(k), cyano, nitro, haloalkyl, haloalkoxy, halo,—NR^(k)R^(m), —OC(═O)NR^(k)R^(m), —C(═O)NR^(k)R^(m), —NR^(k)C(═O)R^(m),—SR^(k), —S(═O)R^(n), —S(O)₂R^(n), —OC(═O)R^(k), —C(═O)OR^(k),—C(═O)R^(k), phenyl, benzyl, phenyloxy, or benzyloxy, wherein R^(k) andR^(m) are selected from hydrogen, lower alkyl, hydroxy(lower alkyl),halo(lower alkyl), cyano(lower alkyl), and amino(lower alkyl), and R^(n)is lower alkyl.

As used herein, “alkylene” refers to a bivalent alkyl radical having thegeneral formula —(CH₂)_(n)—, where n is 1 to 10. Non-limiting examplesinclude methylene, dimethylene, trimethylene, tetramethylene,pentamethylene, and hexamethylene. The term “lower alkylene” hereinrefers to those alkylene groups having from about 1 to about 6 carbonatoms. “Substituted alkylene” refers to an alkylene group substitutedwith one or more substituents, preferably 1 to 4 substituents, at anyavailable point of attachment. Exemplary substituents include, but arenot limited to alkyl, substituted alkyl, and those groups recited aboveas exemplary alkyl substituents.

When the term alkyl is used as a subscript following anotherparticularly-named group, as in “arylalkyl”, “substituted arylalkyl”,“cycloalkylalkyl”, etc., or as in hydroxy(lower alkyl), this refers toan alkyl group having one or two (preferably one) substituents selectedfrom the other, particularly-named group. Thus, for example, arylalkylincludes benzyl, biphenyl and phenylethyl. A “substituted arylalkyl”will be substituted on the alkyl portion of the radical with one or moregroups selected from those recited above for alkyl, and/or will besubstituted on the aryl portion of the radical with one or more groupsselected from those recited below for substituted aryl.

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary groups include ethenyl or allyl.“Substituted alkenyl” refers to an alkenyl group substituted with one ormore substituents, preferably 1 to 4 substituents, at any availablepoint of attachment. Exemplary substituents include, but are not limitedto, alkyl, substituted alkyl, and those groups recited above asexemplary alkyl substituents.

The term “alkenylene” refers to a straight or branched chain bivalenthydrocarbon radical containing from 2 to 12 carbon atoms and at leastone carbon-carbon double bond. Exemplary groups include ethenylene orallylene. “Substituted alkenylene” refers to an alkenylene groupsubstituted with one or more substituents, preferably 1 to 4substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, alkyl, substituted alkyl,and those groups recited above as exemplary alkyl substituents.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least one carbon tocarbon triple bond. Exemplary groups include ethynyl. “Substitutedalkynyl” refers to an alkynyl group substituted with one or moresubstituents, preferably 1 to 4 substituents, at any available point ofattachment. Exemplary substituents include, but are not limited to,alkyl, substituted alkyl, and those groups recited above as exemplaryalkyl substituents.

The term “alkynylene” refers to a straight or branched chain bivalenthydrocarbon radical containing from 2 to 12 carbon atoms and at leastone carbon to carbon triple bond. Exemplary groups include ethynylene.“Substituted alkynylene” refers to an alkynylene group substituted withone or more substituents, preferably 1 to 4 substituents, at anyavailable point of attachment. Exemplary substituents include, but arenot limited to, alkyl, substituted alkyl, and those groups recited aboveas exemplary alkyl substituents.

The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbongroup containing from 1 to 3 rings and 3 to 8 carbons per ring.Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. The term “cycloalkyl” also includes groups having acarbon-carbon bridge of one to two bridgehead carbon atoms, and bicyclicand tricyclic groups in which at least one of the rings is a saturated,carbon-containing ring, in which case the second or third ring may becarbocyclic or heterocyclic, provided that the point of attachment is tothe cycloalkyl group. The further rings may be attached to thesaturated, carbon-containing ring in a spiro or fused fashion.“Substituted cycloalkyl” refers to a cycloalkyl group substituted withone or more substituents, preferably 1 to 4 substituents, at anyavailable point of attachment. Exemplary substituents include, but arenot limited to, alkyl, substituted alkyl, oxo(═O), and those groupsrecited above as exemplary alkyl substituents.

The term “cycloalkylene” refers to a bivalent cycloalkyl group asdefined above. Exemplary groups include cyclopropylene, cyclobutylene,cyclopentylene and cyclohexylene. “Substituted cycloalkylene” refers toa cycloalkylene group substituted with one or more substituents,preferably 1 to 4 substituents, at any available point of attachmentselected from those recited for substituted cycloalkyl. The term“cycloalkenyl” refers to a partially unsaturated cyclic hydrocarbongroup containing 1 to 3 rings and 4 to 8 carbons per ring. Exemplarygroups include cyclobutenyl, cyclopentenyl, and cyclohexenyl. The term“cycloalkenyl” also includes bicyclic and tricyclic groups in which atleast one of the rings is a partially unsaturated, carbon-containingring and the second or third ring may be carbocyclic or heterocyclic,provided that the point of attachment is to the cycloalkenyl group.“Substituted cycloalkenyl” refers to a cycloalkenyl group substitutedwith one or more substituents, preferably 1 to 4 substituents, at anyavailable point of attachment selected from those recited above forcycloalkyl groups.

The term “cycloalkenylene” refers to a bivalent cycloalkenyl group, asdefined above. Exemplary groups include cyclobutenylene,cyclopentenylene, and cyclohexenylene. “Substituted cycloalkenylene”refers to a cycloalkenylene group substituted with one or moresubstituents, preferably 1 to 4 substituents, at any available point ofattachment, selected from those recited for substituted cycloalkyl.

The terms “alkoxy” or “alkylthio” refer to an alkyl group as describedabove bonded through an oxygen linkage (—O—) or a sulfur linkage (—S—),respectively. The terms “substituted alkoxy” or “substituted alkylthio”refer to a substituted alkyl group as described above bonded through anoxygen or sulfur linkage, respectively. “Thiol” refers to —SH.

The term “alkoxycarbonyl” refers to an alkoxy group bonded through acarbonyl group (i.e., —C(═O)—O-alkyl).

The term “alkylcarbonyl” refers to an alkyl group bonded through acarbonyl group (i.e., —C(═O)alkyl).

The term “alkylcarbonyloxy” refers to an alkylcarbonyl group bondedthrough an oxygen linkage (i.e., —O—C(═O)-alkyl).

The term “amido” refers to the group —NHC(═O)H, and amidinyl refers tothe group —C(═NH)(NH₂). A “substituted amido” refers to the group—NR^(p)C(═O)R^(q), and a “substituted amidinyl” refers to the group—C(═NR^(p))(NR^(q)R^(r)), wherein R^(p), R^(q), and R^(r) are selectedfrom hydrogen, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, aryl, substituted aryl, heterocyclo, and substitutedheterocyclo, provided that at least one of R^(p), R^(q), and R^(r) isother than hydrogen.

The term “aryl” encompasses monocyclic and polycyclic aryl groups. Theterm “monocyclic aryl” refers to phenyl, and the term “polycyclic aryl”refers to napthyl and anthracenyl, to phenyl rings having at least asecond ring fused thereto, and to napthyl rings having a third ringfused thereto. In the case of a polycyclic aryl consisting of a phenylring having a second or third ring fused thereto, or a napthyl ringhaving a third ring fused thereto, the additional rings may be aromaticor non-aromatic carbocyclic or heterocyclic rings, provided that in suchcases the point of attachment will be to the carbocyclic aromatic ring.Additionally, a ring carbon atom of the second and third further ringsmay be replaced with a carbonyl [—C(═O)group] (e.g., when such rings arenon-aromatic). “Substituted aryl” refers to an aryl group substituted byone or more substituents, preferably 1 to 4 substituents (morepreferably 1 or 2), at any point of attachment of any ring, selectedfrom alkyl, substituted alkyl, and the substituents recited above forsubstituted alkyl groups.

Accordingly, examples of aryl groups include:

and the like.

The term “arylene” refers to bivalent aryl groups as defined above.

“Carbamoyl” refers to the group —C(═O)—NR^(h)R^(i), wherein R^(h) andR^(i) are selected from hydrogen, alkyl, cycloalkyl, aryl, andheterocyclo.

“Carbamate” refers to the group —O—C(═O)—NR^(h)R^(i), and “urea” refersto the groups NH—C(═O)—NR^(h)R^(i) and N(alkyl)-C(═O)—NR^(h)R^(i),wherein R^(h) and R^(i) are selected from the same groups recited forcarbamoyl.

“Substituted carbamoyl”, “substituted carbamate”, and “substituted urea”refer to the groups —C(═O)—NR^(h)R^(i), —O—C(═O)—NR^(h)R^(i), and—N(R^(j))—C(═O)—NR^(h)R^(i), respectively, wherein R^(h), R^(i), andR^(j) are selected from hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heterocyclo, andsubstituted heterocyclo, provided that at least one of R^(h), R^(i), andR^(j) is substituted alkyl, substituted cycloalkyl, substituted aryl, orsubstituted heterocyclo.

The terms “heterocycle”, “heterocyclic” and “heterocyclo” refer to fullysaturated, partially unsaturated, or fully unsaturated, includingaromatic (i.e., “heteroaryl”) cyclic groups (for example, 3 to 7membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16 memberedtricyclic ring systems) which have at least one heteroatom in at leastone carbon atom-containing ring. Thus, the term “heteroaryl” is a subsetof heterocyclo groups. Each ring of the heterocyclic group containing aheteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogenatoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. (The term “heteroarylium” refers to aheteroaryl group bearing a quaternary nitrogen atom and thus a positivecharge.) Additionally, one or more (preferably one) carbon ring atoms ofthe heterocyclo ring may, as valence allows, be replaced with carbonylgroup, i.e., —C(═O)—. The heterocyclic group may be attached to theremainder of the molecule at any heteroatom or carbon atom of the ringor ring system.

Exemplary monocyclic heterocyclic groups include ethylene oxide,azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl,hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.

Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl,benzothiazolyl, benzodioxolyl, benzoxazolyl, benzoxadiazolyl,benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl,benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydrobenzodioxinyl, dihydrodioxidobenzothiophenyl, dihydroisoindolyl,dihydroindolyl, dihydroquinolinyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyland the like. Exemplary tricyclic heterocyclic groups includecarbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl,phenanthridinyl, xanthenyl and the like. The term “heterocyclene” refersto bivalent heterocycle groups as defined above.

“Substituted heterocycle”, “substituted heterocyclic”, and “substitutedheterocyclo” (such as “substituted heteroaryl”) refer to heterocycle,heterocyclic or heterocyclo groups substituted with one or moresubstituents, preferably 1 to 4 substituents, at any available point ofattachment, wherein the substituents are selected from those recitedabove for substituted cycloalkyl groups.

The term “quaternary nitrogen” refers to a tetravalent positivelycharged nitrogen atom including, for example, the positively chargednitrogen in a tetraalkylammonium group (e.g., tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.,N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).

The term “heteroaryl” refers to five and six member monocyclic aromaticheterocyclo groups, as well as bicyclic and tricyclic heterocyclic ringsystems in which the point of attachment of the ring system to anothergroup is via a five or six member aromatic ring of the ring system.Thus, for example, the term heteroaryl includes groups such as five orsix member heteroaryl groups, such as thienyl, pyrrolyl, oxazolyl,pyridyl, pyrazinyl, and the like, wherein fused rings completingbicyclic and tricyclic groups may contain only carbon atoms and may besaturated, partially saturated, or unsaturated. Heteroaryl groups whichare bicyclic or tricyclic must include at least one fully aromatic ringbut the other fused ring or rings may be aromatic or non-aromatic. Theterm “substituted heteroaryl” refers to five and six member monocyclicaromatic heterocyclo groups substituted with one or more substituents,preferably 1 to 4 substituents, at any available point of attachment,wherein the substituents are selected from those recited above forsubstituted cycloalkyl groups.

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl,furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and thelike.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl, and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “halogen” or “halo” refer to chlorine, bromine, fluorine oriodine.

The terms “hydroxylamine” and “hydroxylamide” refer to the groups —NH—OHand —C(═O)—NH—OH, respectively.

Unless otherwise indicated, the term “substituted amino” as employedherein alone or as part of another group refers to amino substitutedwith one or two substituents, which may be the same or different, suchas alkyl, aryl, arylalkyl, heterocyclo, heteroaryl, heteroarylalkyl,cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, thioalkyl, —C(O)R^(f),—C(═O)OR^(f), —C(═O)NR^(f)R^(g), —S(O)₂R^(f), —S(O)₂OR^(f), or—S(O)₂NR^(f)R^(g), wherein R^(f) and R^(g) can be hydrogen, alkyl,substituted alkyl, aryl, substituted aryl or heterocyclo. Thesesubstituents may be further substituted with a carboxylic acid and/orany of the substituents for alkyl as set out above. In addition, theamino substituents may be taken together with the nitrogen atom to whichthey are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, aryl,heterocyclo, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, amino,—C(O)R^(f), —C(═O)OR^(f), —C(═O)NR^(f)R^(g), —S(O)₂R^(f), —S(O)₂OR^(f),or —S(O)₂NR^(f)R^(g), wherein R^(f) and R^(g) can be hydrogen, alkyl,substituted alkyl, aryl, substituted aryl or heterocyclo.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “haloalkyl” means an alkyl having one or more halosubstituents.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes —OCF₃.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted, in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

When it is stated that a group may be “optionally substituted”, this isintended to include unsubstituted groups and substituted groups whereinthe substituents are selected from those recited above for theparticularly named group. Thus, when reference is made to an optionallysubstituted aryl, it is intended to refer to unsubstituted aryl groups,such as phenyl or naphthyl, and such groups having one or more(preferably 1 to 4, and more preferably 1 or 2) substituents selectedfrom alkyl, substituted alkyl, and those substituents recited forsubstituted alkyl groups. When the term “optionally substituted”precedes a Markush group, the term “optionally substituted” is intendedto modify each one of the species recited in the Markush group. Thus,for example, the phrase “optionally substituted aryl, cycloalkyl, orheterocycle” includes aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, heterocycle, and substituted heterocycle.

Among the compounds of the invention, in the case of a compound whichhas a sulfide, the sulfur atom may be converted into oxido at anappropriate oxidation state, and all of these oxido derivatives areincluded herein.

“N-oxide” refers to compounds wherein the basic nitrogen atom of eithera heteroaromatic ring or tertiary amine is oxidized to give a quaternarynitrogen bearing a positive formal charge and an attached oxygen atombearing a negative formal charge.

“Solvate” refers to a molecular or ionic complex of molecules or ions ofsolvent with molecules or ions of solute. It should further beunderstood that solvates (e.g., hydrates) of the compounds of Formula(I) are also within the scope of the present invention. Methods ofsolvation are generally known in the art.

When a functional group is termed “protected”, this means that the groupis in modified form to mitigate, especially preclude, undesired sidereactions at the protected site. Suitable protecting groups for themethods and compounds described herein include, without limitation,those described in standard textbooks, such as Greene, T. W. et al.,Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

Carboxylate anion refers to a negatively charged group —COO⁻.

The compounds of the present invention may form salts which are alsowithin the scope of this invention. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred, althoughother salts are also useful, e.g., in isolating or purifying thecompounds of this invention.

The compounds of the present invention may form salts with alkali metalssuch as sodium, potassium, and lithium; with alkaline earth metals suchas calcium and magnesium; and with organic bases such asdicyclohexylamine, tributylamine, pyridine, and amino acids such asarginine, lysine, and the like. Such salts can be formed as known tothose skilled in the art.

The compounds of the present invention may form salts with a variety oforganic and inorganic acids. Such salts include those formed withhydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuricacid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid,benzenesulfonic acid, toluenesulfonic acid, and various others (e.g.,nitrates, phosphates, borates, tartrates, citrates, succinates,benzoates, ascorbates, salicylates, and the like). Such salts can beformed as known to those skilled in the art. Salt forms of the compoundsmay be advantageous for improving the compound dissolution rate and oralbioavailability.

In addition, zwitterions (“inner salts”) may be formed.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The definition of compounds according to the invention embraces all thepossible stereoisomers and their mixtures; it also embraces the racemicforms and the isolated optical isomers having the specified activity.The racemic forms can be resolved by physical methods, such as, forexample, fractional crystallization, separation, or crystallization ofdiastereomeric derivatives or separation by chiral columnchromatography. The individual optical isomers can be obtained from theracemates from the conventional methods, such as, for example, saltformation with an optically active acid followed by crystallization.

Particular Compounds

One embodiment of the present invention relates to a compound of Formula(I)

or an enantiomer, diastereomer or a pharmaceutically-acceptable saltthereof wherein:

L and M are as defined above;

ring A is an aryl or heteroaryl selected from the group consisting ofphenyl, indole, azaindole, quinoline, thiazole, thiophene, benzofuranand benzothiophene;

R¹, R² and R³ are as defined above;

R⁴ is selected from the group consisting of hydrogen; hydroxyl; halo;haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens (forexample, CF₃, CH₂CF₃, and CF₂CH₃); CO₂R¹⁰, CONR¹⁰R²⁰ or NR¹⁰R¹⁰R²⁰wherein each of R¹⁰ and R²⁰ are independently selected from the groupconsisting of H, C1-C6 straight or branched chain alkyl, C1-C4 straightor branched chain alkyl amino, C1-C4 straight or branched chain dialkylamino, C 1-C4 straight or branched chain alkyl with an OH group, C4-C10heterocyclo with 1-3 members selected from the group consisting of N, Sand O, provided there is no O—O or S—S portion, optionally substitutedamino, and alkyl amino;

m is as defined above with particular examples of fused rings formed by2 of R¹ being a ring selected from the group consisting of an optionallyfused and optionally substituted cycloalkyl, benzyl, benzoyl, aryl,heterocyclo and heteroaryl;

n is as defined above;

B is as defined above, particularly wherein q is 0.

In another embodiment, a particular value for R⁴ is selected from thegroup consisting of hydrogen; hydroxyl, halo, haloalkyl wherein thehaloalkyls have 1-3 carbons and 1-5 halogens, CO₂R¹¹, CONR¹¹R¹² andNR¹¹R¹² wherein each of R¹¹ and R¹² are independently selected from thegroup consisting of H, C1-C6 straight or branched chain alkyl, C1-C4straight or branched chain alkyl amino, C1-C4 straight or branched chaindialkyl amino, C 1-C4 straight or branched chain alkyl with an OH group;and C4-C10 heterocyclo with 1-3 members selected from the groupconsisting of N, S and O, provided there are no O—O or S—S bonds in R⁴and the heterocyclo group can be optionally substituted with a memberselected from the group consisting of C1-C4 alkyl, optionallysubstituted amino, and alkyl amino.

In another particular embodiment for Formula (I),

Q is a bond when L is —N— and M is —C═;

ring A is selected from phenyl, indole and pyrrolo[2,3-b]pyridine;

q is 0;

m is 1 or 2;

n is 1 or 3;

R¹ is halo, halo-C₁₋₃ alkyl (for example, those having 1-3 carbons and1-5 halogens such as CF₃, CH₂CF₃, and CF₂CH₃) or optionally substitutedC₁₋₃ alkyl;

R² is selected from the group consisting of halo, halo-C₁₋₃ alkyl (forexample, those having 1-3 carbons and 1-5 halogens such as CF₃, CH₂CF₃,and CF₂CH₃), optionally substituted C₁₋₃ alkyl, C₁₋₃ alkoxy and—[C(O)]₂NR⁷R⁸ wherein —[C(O)]₂NR⁷R⁸ has the meaning defined above; and

R³ and R⁴ are each hydrogen.

One particular group of compounds of the present invention includesthose selected from the group consisting of:

In yet another particular embodiment of Formula (I),

Q is a bond when L is —C═ and M is —N—;

q is O;

R¹ is halo or C₁₋₃ alkyl;

R² is selected from the group consisting of halo, halo-C₁₋₃ alkyl (forexample, those having 1-3 carbons and 1-5 halogens such as CF₃, CH₂CF₃,and CF₂CH₃), optionally substituted C₁₋₃ alkyl, optionally substitutedC₁₋₃ alkoxy, and —[C(O)]₂NR⁷R⁸ wherein —[C(O)]₂NR⁷R⁸ has the meaningdefined above;

R³ is hydrogen;

R⁴ is hydrogen or —C(O)NR⁹R¹⁰ wherein —C(O)NR⁹R¹⁰ has the same meaningas defined above;

ring A is selected from the group consisting of phenyl, indole,indazole, benzo-imidazole, pyrrolo[2,3-b]pyridine and2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.

Still another particular group of compounds are those selected from thegroup consisting of:

In another more particular embodiment of the invention as shown inFormula (I):

Q is —N═ when L and M are both —C═;

ring A is an indole;

m is 2;

n is 3;

q is 0;

R¹ is halo;

R² is halo, C₁₋₃ alkyl or —[C(O)]₂NR⁷R⁸ wherein each of R⁷ and R⁸ isindependently a C₁₋₃ alkyl; and

R³ and R⁴ are each hydrogen.

Other embodiments of this invention include pharmaceutical compositionscomprising at least one compound of Formula (I) and a pharmaceuticallyacceptable carrier or diluent.

Utility

The compounds of the invention are selective inhibitors of p38 kinase,and in particular, isoforms p38α and p38β. Accordingly, compounds ofFormula (I) have utility in treating conditions associated with p38kinase activity. Such conditions include diseases or disorders in whichcytokine levels are modulated as a consequence of intracellularsignaling via p38, and in particular diseases that are associated withan overproduction of cytokines IL-1, IL-4, IL-8 and TNF-α. As usedherein, the terms “treating” or “treatment” encompass responsive and/orprophylaxis measures addressed to the disease state and/or its symptoms,e.g. measures designed to inhibit or delay the onset of the disease ordisorder, achieve a full or partial reduction of the symptoms or diseasestate, and/or alleviate, lessen, or cure the disease and/or itssymptoms. When reference is made herein to inhibition of “p-38α/βkinase”, this means that either or both p38α and p38β kinase areinhibited.

In view of their activity as inhibitors of p-38α/β kinase, compounds ofFormula (I) are useful in treating inflammatory diseases, autoimmunediseases, destructive bone disorders, proliferative disorders,angiogenic disorders, infectious diseases, neurodegenerative diseases,viral diseases, and ischemia reperfusion conditions.

More particularly, the inventive compounds may be used to treatinflammatory diseases including, but not limited to, arthritis (e.g.,rheumatoid arthritis, lyme disease arthritis, osteoarthritis, traumaticarthritis, rubella arthritis, psoriatic arthritis, gouty arthritis, andother arthritic conditions), glomerulonephritis, pancreatitis (acute orchronic), diabetes, diabetic retinopathy, macular degeneration,conjunctivitis, aplastic anemia, thrombocytopenia, gastritis, chronicthyroiditis, chronic active hepatitis, multiple sclerosis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, cachexia (includingcachexia secondary to infection, cancer, or heart disease), periodontaldisease, Alzheimer's disease, Parkinson's disease, keloid formation,pulmonary sarcoidosis, myasthenia gravis, inflammatory reaction inducedby endotoxin, Reiter's syndrome, gout, acute synovitis, diseasescharacterized by massive neutrophil infiltration, ankylosingspondylitis, influenza, cerebral malaria, silicosis, bone resorptiondisease, fever, myalgias due to infection, osteoporosis, multiplemyeloma-related bone disorder, neurodegenerative disease caused bytraumatic injury, and traumatic brain injury.

The inventive compounds may also be used to treat acute or chronic graftvs. host reactions (e.g., pancreatic islet allograft), acute or chronictransplant rejection (e.g., kidney, liver, heart, lung, pancreas, bonemarrow, cornea, small bowel, skin allografts, skin homografts,heterografts, and/or cells derived from such organs), and skinconditions including, but not limited to, scar tissue formation, eczema,atopic dermatitis, contact dermatitis, urticaria, scleroderma,scleraclerma, and psoriasis. The inventive compounds also may be used totreat allergies and respiratory conditions, including asthma, acuterespiratory distress syndrome, hay fever, allergic rhinitis, and anychronic pulmonary inflammatory disease, such as chronic obstructivepulmonary disease. The compounds further may be used to treat steroidresistance in asthma and allergies.

Additionally, the inventive compounds may be used to treat inflammationassociated with autoimmune diseases including, but not limited to,systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),and Graves' disease. The inventive compounds may be used to treatinfectious diseases such as sepsis, septic shock, Shigellosis, andHeliobacter Pylori.

The instant compounds may be used to treat viral diseases includingherpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2),cytomegalovirus, Epstein-Barr, human immunodeficiency virus (HIV), acutehepatitis infection (including hepatitis A, hepatitis B, and hepatitisC), HIV infection and CMV retinitis, AIDS<ARC or malignancy, and herpes.

The inventive compounds also may be used to treat angiogenic disordersincluding solid tumors, ocular neovasculization and infantilehaemangiomas. In addition, p38 inhibitors of this invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2). Accordingly, additional conditions that may be treated with theinventive compounds include edema, analgesia and pain, such asneuromuscular pain, headache, pain caused by cancer or surgery, dentalpain and arthritis pain. In view of their COX-2 inhibitory activity, theinventive compounds also may be used to treat cancer, including, withoutlimitation, epithelial cancer and adenocarcinoma.

Additionally, the compounds of this invention are useful to treatischemia, including ischemia resulting from vascular occlusion, cerebralinfarction, stroke, and related cerebral vascular diseases (includingcerebrovascular accident and transient ischemic attack). Accordingly,the compounds may be used to treat myocardial infarction, coronaryartery disease, non-Q wave MI, congestive heart failure, ventricularhypertrophy, cardiac arrhythmias, unstable angina, chronic stableangina, Prinzmetal's angina, high blood pressure, intermittentclaudication, silent ischemia, cardiac hypertrophy, and peripheralocclusive arterial disease (e.g., peripheral arterial disease, criticalleg ischemia, prevention of amputation, and prevention of cardiovascularmorbidity such as MI, stroke or death).

Additionally, in view of their activity in treating ischemia, thecompounds of the invention may be useful to treat symptoms orconsequences occurring from thrombosis, atherosclerosis, peripheralarterial disease, and thrombotic or thromboembolic symptoms orconsequences associated with and/or caused by one or more of thefollowing: thromboembolic stroke (including that resulting from atrialfibrillation or from ventricular or aortic mural thrombus), venousthrombosis (including deep vein thrombosis), arterial thrombosis,cerebral thrombosis, pulmonary embolism, cerebral embolism,thrombophilia (e.g., Factor V Leiden, and homocystinenimia), coagulationsyndromes and coagulopathies (e.g., disseminated intravascularcoagulation), restenosis (e.g., following arterial injury inducedendogenously or exogenously), atrial fibrillation, and ventricularenlargement (including dilated cardiac myopathy and heart failure). Thecompounds of the invention also may be used to treat symptoms orconsequences of atherosclerotic diseases and disorders, such asatherosclerotic vascular disease, atherosclerotic plaque rupture,atherosclerotic plaque formation, transplant atherosclerosis, andvascular remodeling atherosclerosis. The compounds of the inventionfurther may be used to treat symptoms or consequences of thrombotic orthromboembolic conditions associated with cancer, surgery, inflammation,systematic infection, artificial surfaces (such as stents, bloodoxygenators, shunts, vascular access ports, vascular grafts, artificialvalves, etc.), interventional cardiology such as percutaneoustransluminal coronary angioplasty (PTCA), immobility, medication (suchas oral contraceptives, hormone replacement therapy, and heparin),pregnancy and fetal loss, and diabetic complications includingretinopathy, nephropathy, and neuropathy.

The compounds of the present invention may be used for the preservationof tissue, for example, the preservation of tissue as relates to organtransplantation and surgical manipulation. The compounds may be used totreat diseases or disorders in other tissues or muscles that areassociated with ischemic conditions and/or to enhance the strength orstability of tissue and muscles. For example, the compounds may be usedto treat muscle cell damage and necrosis and/or to enhance athletes'performance.

Additional diseases and disorders that may be treated with the inventivecompounds include irritable bowel syndrome, leukemia, CNS disordersassociated with cerebral ischemia, such as cerebral infarction, cerebraledema and the like, and diseases associated with proliferation of smoothmuscle cells, mesangial cells, and fibroblasts. Such diseases includerenal fibrosis, hepatic fibrosis, prostate hypertrophy, and pulmonaryfibrosis.

The inventive compounds also may be used to treat veterinary viralinfections, such as lentivirus infections, including, but not limitedto, equine infectious anemia virus; or retro virus infections, includingfeline immunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “p38 associated condition” or “p38 associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is modulated by p38 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof aneffective amount of at least one compound of Formula (I), or apharmaceutically-acceptable salt thereof. The methods of treating p38kinase-associated conditions may comprise administering compounds ofFormula (I) alone or in combination with each other and/or othersuitable therapeutic agents such as anti-inflammatory drugs,antibiotics, anti-viral agents, anti-oxidants, cholesterol/lipidlowering agents, anti-tumor agents including antiproliferative agents,and agents used to treat ischemia.

Examples of suitable other anti-inflammatory agents with which theinventive compounds may be used include aspirin, cromolyn, nedocromil,theophylline, zileuton, zafirlukast, monteleukast, pranleukast,indomethacin, and lipoxygenase inhibitors; non-steroidalanti-inflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); TNF-αinhibitors (such as tenidap and rapamycin or derivatives thereof), orTNF-α antagonists (e.g., infliximab, enbrel, D2E7, OR1384), cytokinemodulators (e.g., TNF-alpha converting enzyme [TACE] inhibitors,Interleukin-1 converting enzyme (ICE) inhibitors, Interleukin-1 receptorantagonists), prednisone, dexamethasone, Enbrel®, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen®,Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists (LEA29Y), CD40ligand antagonists, IMPDH inhibitors (such as mycophenolate [CellCept®]and VX-497), integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1,prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), other p38 mitogen-activated proteinkinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, therapies for the treatment of irritable bowel syndrome(e.g., Zelmac®, Zelnorm®, and Maxi-K openers such as those disclosed inU.S. Pat. No. 6,184,231 B1), or other NF-κB inhibitors (such calphostin,CSAIDs, and quinoxalines as disclosed in U.S. Pat. No. 4,200,750);corticosteroids (such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide, dexamethasone, prednisone, and dexamethasone);disassociated steroids; chemokine receptor modulators (including CCR1,CCR2, CCR3, CCR4, and CXCR2 receptor antagonists); secretory andcytosolic phospholipase A2 inhibitors, VLA4 antagonists,glucocorticoids, salicylates, nitric oxide, and otherimmunosuppressants; and nuclear translocation inhibitors, such asdeoxyspergualin (DSG).

To treat pain, the inventive compounds may be used in combination withaspirin, NSAIDs, or with 5-HT 1 receptor agonists such as buspirone,sumitriptan, eletriptan or rizatriptan.

Examples of suitable antibiotics with which the inventive compounds maybe used include β-lactams (e.g., penicillins, cephalosporins andcarbopenams); β-lactam and lactamase inhibitors (e.g., augmentin);aminoglycosides (e.g., tobramycin and streptomycin); macrolides (e.g.,erythromycin and azithromycin); quinolones (e.g., cipro and tequin);peptides and deptopeptides (e.g., vancomycin, synercid and daptomycin);metabolite-based antibiotics (e.g., sulfonamides and trimetoprim);polyring systems (e.g., tetracyclins and rifampins); protein synthesisinhibitors (e.g. zyvox, chlorophenicol, clindamycin, etc.); andnitro-class antibiotics (e.g., nitrofurans and nitroimidazoles).

Examples of suitable antiviral agents for use with the inventivecompounds include nucleoside-based inhibitors, protease-basedinhibitors, and viral-assembly inhibitors.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate,risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligandantagonists, calcium sensing receptor antagonists, TRAP inhibitors,selective estrogen receptor modulators (SERM) and AP-1 inhibitors.

Examples of suitable anti-oxidants for use in combination with thecompounds of the present invention include lipid peroxidation inhibitorssuch as probucol, BO-653, Vitamin A, Vitamin E, AGI-1067, and α-lipoicacid.

A further use of the compounds of this invention is in combination withsteroidal or non-steroidal progesterone receptor agonists (“PRA”), suchas levonorgestrel, medroxyprogesterone acetate (MPA).

The inventive compounds also may be used in combination withanti-diabetic agents, such as biguanides (e.g., metformin), glucosidaseinhibitors (e.g., acarbose), insulins (including insulin secretagoguesor insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas(e.g., glimepiride, glyburide and glipizide), biguanide/glyburidecombinations (e.g., glucovance), thiazolidinediones (e.g., troglitazone,rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gammaagonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitorsof fatty acid binding protein (aP2) such as those disclosed in U.S. Pat.No. 6,548,529 and assigned to the present assignee, glucagon-likepeptide-1 (GLP-1), glucagon phosphorylase, and dipeptidyl peptidase IV(DP4) inhibitors.

In addition, the compounds may be used with agents that increase thelevels of cAMP or cGMP in cells for a therapeutic benefit. For example,the compounds of the invention may have advantageous effects when usedin combination with phosphodiesterase inhibitors, including PDE1inhibitors (such as those described in Journal of Medicinal Chemistry,Vol. 40, pp. 2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (suchas revizinone, pimobendan, or olprinone), PDE4 inhibitors (such asrolipram, cilomilast, or piclamilast), PDE7 inhibitors, or other PDEinhibitors such as dipyridamole, cilostazol, sildenafil, denbutyline,theophylline (1,2-dimethylxanthine), ARIFLO™ (i.e.,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid), arofyline, roflumilast, C-11294A, CDC-801, BAY-19-8004,cipamfylline, SCH351591, YM-976, PD-189659, mesiopram, pumafentrine,CDC-998, IC-485, and KW-4490.

The inventive compounds may also be useful in combination withanticancer strategies and chemotherapies such as taxol and/or cisplatin.The compounds may be used in conjunction with anti-tumor agents such aspaclitaxel, adriamycin, epothilones, cisplatin, and carboplatin.

In view of their usefulness in treating ischemia, the inventivecompounds may be used in combination with agents for inhibitingF1F0-ATPase, including efrapeptin, oligomycin, autovertin B, azide, andcompounds described in U.S. Publication No. 2004-0039033A1, publishedFeb. 26, 2004, and assigned to the present assignee; alpha- orbeta-adrenergic blockers (such as propranolol, nadolol, carvedilol, andprazosin), or -β-adrenergic agonists (such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pirbuterol, and fenoterol);antianginal agents such as nitrates, for example, sodium nitrates,nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, andnitrovasodilator; antiarrhythmic agents including Class I agents (suchas propafenone); Class II agents (propranolol); Class III agents (suchas sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IVagents (such as ditiazem and verapamil); K⁺ channel modulators such asIAch inhibitors and inhibitors of the Kν1 subfamily of K⁺ channelopeners such as IKur inhibitors (e.g., compounds disclosed in U.S. Pat.No. 6,706,720, assigned to the present assignee); and gap-junctionmodulators such as connections; anticoagulant or antithrombotic agentsincluding aspirin, warfarin, ximelagatran, low molecular weight heparins(such as lovenox, enoxaparin, and dalteparin), anti-platelet agents suchas GPIIb/GPIIIa blockers (e.g., abciximab, eptifibatide and tirofiban),thromboxane receptor antagonists (e.g., ifetroban), P2Y1 and P2Y12antagonists (e.g., clopidogrel, ticlopidine, CS-747, andaspirin/clopidogrel combinations), and Factor Xa inhibitors (e.g.,fondaprinux); and diuretics such as sodium-hydrogen exchange inhibitors,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetamide, triamtrenene and amiloride.

Additionally, the inventive compounds may be used in combination withlipid profile modulators and antiatheroaclerotic agents includingHMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin[Nissan/Kowa]), ZD-4522 (a.k.a. rosuvastatin, itavastatin orvisastatin), pravachol, squalene synthetase inhibitors, fibrates, bileacid sequestrants (such as questran), niacin and niacin/statincombinations, lipoxygenase inhibitors, ileal Na+/bile acid cotransporterinhibitors, ACAT1 inhibitors, ACAT2 inhibitors, dual ACAT½ inhibitors,microsomal triglyceride transport protein inhibitors (such as disclosedin U.S. Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), cholesterolabsorption inhibitors (such as Zetia®), cholesterol ester transferprotein inhibitors (e.g., CP-529414), PPAR-delta agonists, PPAR-alphaagonists, dual PPAR-alpha/delta agonists, LXR-alpha agonists, LXR-betaagonists, LXR dual alpha/beta agonists, and SCAP modulators.

The combination of the inventive compounds with other therapeutic agentsmay prove to have additive and synergistic effects. The combination maybe advantageous to increase the efficacy of the administration ordecrease the dosage to reduce possible side-effects.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds.

The present invention also provides pharmaceutical compositions capableof treating p38-kinase associated conditions, including TNF-α, IL-1,and/or IL-8 mediated conditions, as described above. The inventivecompositions may contain other therapeutic agents as described above.Pharmaceutical compositions may be formulated by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(e.g., excipients, binders, preservatives, stabilizers, flavors, etc.)according to techniques such as those well known in the art ofpharmaceutical formulations.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; buccally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934). Lubricants, glidants, flavors, coloring agents andstabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for a mammal of from about 0.05 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. It will be understood that the specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors, including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats, horses,and the like. Thus, when the term “patient” is used herein, this term isintended to include all subjects, most preferably mammalian species,that are affected by mediation of p38 enzyme levels.

Compounds of Formula (I), including the compounds described in theexamples herein, have been tested in one or more of the assays describedbelow and have shown activity as inhibitors of p38α/β enzymes and TNF-α.

In general, preferred compounds of the present invention, such asparticular compounds disclosed in the following examples, have beenidentified to inhibit the activity of one or more of p38α/β enzymes.Potencies can be calculated and expressed as either inhibition constants(K_(i) values) or as IC₅₀ (inhibitory concentration 50%) values, andrefer to activity measured employing the in vitro assay systemsdescribed herein. Exemplary values for compounds that inhibit theactivity of p38α/β enzymes include concentration equivalent to, or morepotent than, 10 μM, preferably 1 μM, and more preferably 0.1 μM, therebydemonstrating particular compounds of the present invention as effectiveinhibitors of p38 α/β enzymes.

Biological Assays Generation of p38 Kinases

cDNAs of human p38α, β, and γ isozymes were cloned by PCR. These cDNAswere subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusionprotein was expressed in E. Coli and purified from bacterial pellets byaffinity chromatography using glutathione agarose. p38 fusion proteinwas activated by incubating with constitutively active MKK6. Active p38was separated from MKK6 by affinity chromatography. Constitutivelyactive MKK6 was generated according to Raingeaud et al. [Mol. Cell.Biol., 1247-1255 (1996)].

TNF-α Production by LPS-Stimulated PBMCs

Heparinized human whole blood was obtained from healthy volunteers.Peripheral blood mononuclear cells (PBMCs) were purified from humanwhole blood by Ficoll-Hypaque density gradient centrifugation andresuspended at a concentration of 5×10⁶/ml in assay medium (RPMI mediumcontaining 10% fetal bovine serum). 50 μl of cell suspension wasincubated with 50 μl of test compound (4× concentration in assay mediumcontaining 0.2% DMSO) in 96-well tissue culture plates for 5 minutes atRT. 100 μl of LPS (200 ng/ml stock) was then added to the cellsuspension and the plate was incubated for 6 hours at 37° C. Followingincubation, the culture medium was collected and stored at −20° C. TNF-αconcentration in the medium was quantified using a standard ELISA kit(Pharmingen-San Diego, Calif.). Concentrations of TNF-α and IC₅₀ valuesfor test compounds (concentration of compound that inhibitedLPS-stimulated TNF-α production by 50%) were calculated by linearregression analysis.

p38 Assays

(1) The assays were performed in V-bottomed 96-well plates. The finalassay volume was 60 μl prepared from three 20 μl additions of enzyme,substrates (MBP and ATP) and test compounds in assay buffer (50 mM TrispH 7.5, 10 mM MgCl₂, 50 mM NaCl and 1 mM DTT). Bacterially expressed,activated p38 was pre-incubated with test compounds for 10 min. prior toinitiation of reaction with substrates. The reaction was incubated at25° C. for 45 min. and terminated by adding 5 μl of 0.5 M EDTA to eachsample. The reaction mixture was aspirated onto a pre-wet filtermatusing a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed withPBS. The filtermat was then dried in a microwave oven for 1 min.,treated with MeltilLex A scintillation wax (Wallac), and counted on aMicrobeta scintillation counter Model 1450 (Wallac). Inhibition datawere analyzed by nonlinear least-squares regression using Prizm(GraphPadSoftware). The final concentration of reagents in the assaysare ATP, 1 μM; [γ-³³P]ATP, 3 nM; MBP (Sigma, #M1891), 2 μg/well; p38, 10nM; and DMSO, 0.3%.

(2) In an alternate method, the assays were performed in U-bottom384-well plates. The final assay volume was 30 μl prepared from 15 μladditions of enzyme and substrates (fluoresceinated peptideFL-IPTSPITTTYFFFKKK—OH and ATP) and test compounds in assay buffer (100mM HEPES pH 7.2, 10 mM MgCl₂, 0.015% Brij35 and 4 mM DTT). The reactionwas initiated by the combination of bacterially expressed, activated p38with substrates and test compounds. The reaction was incubated at roomtemperature for 60 min. and terminated by adding 30 μl of 35 mM EDTA toeach sample. The reaction mixture was analyzed on the Caliper LabChip3000 by electrophoretic separation of the fluorescent substrate andphosphorylated product. Inhibition data were calculated by comparison tono enzyme control reactions for 100% inhibition and vehicle-onlyreactions for 0% inhibition. The final concentration of reagents in theassays are ATP, 20 μM; FL-IPTISPITTTYFFFKKK—OH, 1.5 uM; p38, 6 nM; andDMSO, 0.6%.

Abbreviations

For ease of reference, the following abbreviations are employed herein,including the methods of preparation and Examples that follow:

-   ° C.=degrees Celsius-   μL=microliter-   anhyd.=anhydrous-   aq.=aqueous-   Boc=tert-butyloxycarbonyl-   CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   CO₂=carbon dioxide-   d=doublet-   DCE=1,2-dichloroethane-   DCM=dichloromethane-   dd=doublet of doublet-   DEAD=diethyl azodicarboxylate-   DIPEA=diisopropylethylamine-   DMF=dimethyl formamide-   DMSO=dimethyl sulfoxide-   EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   EtOAc=ethyl acetate-   EtOH=ethanol-   g=gram(s)-   h=hour(s)-   HATU=O-(7-Azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium    hexafluorophosphate-   HCl=hydrogen chloride-   HOBt=1-hydroxybenzotriazole hydrate-   HPLC=high performance liquid chromatography-   K₂CO₃=potassium carbonate-   KOH=potassium hydroxide-   KOtBu=potassium t-butoxide-   L=liter-   LCMS=high performance liquid chromatography/mass spectrometry-   M=Molar-   m=multiplet-   m-CPBA=m-chloroperbenzoic acid-   MeOH=methanol-   mg=milligram(s)-   MHz=megahertz-   min=minute(s)-   mL or ml=milliliter-   mmol=millimole(s)-   mol=moles-   MS=mass spectrometry-   N=Normal-   Na₂S₂O₃=sodium thiosulfate-   NaH=sodium hydride-   NaOEt=sodium ethoxide-   NaOH=sodium hydroxide-   NMP=N-methylpyrrolidinone-   NMR=nuclear magnetic resonance-   Pd=palladium-   Pd/C=palladium on carbon-   PmB=para-methoxybenzyl-   POCl₃=phosphorous oxychloride-   p-TsOH=para-toluenesulphonic acid-   Ret. time or t_(R)=retention time (minutes)-   rt=room temperature-   s=singlet-   sat or sat'd=saturated-   sec=second (s)-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TMS=trimethylsilyl

Methods of Preparation

The compounds of the present invention may be synthesized usingconventional techniques known in the art. Advantageously, thesecompounds are conveniently synthesized from readily available startingmaterials. Following are general synthetic schemes for manufacturingcompounds of the present invention. These schemes are illustrative andare not meant to limit the possible techniques one skilled in the artmay use to manufacture compounds disclosed herein. Different methodswill be evident to those skilled in the art. Additionally, the varioussteps in the synthesis may be performed in an alternate sequence ororder to give the desired compound(s). All documents cited areincorporated herein by reference in their entirety.

Compounds of the present invention can be made by many methods, whichwill be known to one skilled in the art of organic chemistry. Ingeneral, the time taken to complete a reaction procedure will be judgedby the person performing the procedure, preferably with the aid ofinformation obtained by monitoring the reaction by methods such as HPLCor TLC. A reaction does not have to go to completion to be useful tothis invention. The preparation of heterocycles useful to this inventionare described in the series of books: “Comprehensive HeterocyclicChemistry. The Structure, Reactions, Synthesis and Uses, of HeterocyclicCompounds” Katritzky, A. R., Rees, C. W. Ed's Pergamon Press New York,First edition 1984, and “Comprehensive Heterocyclic Chemistry II. AReview of the Literature 1982-1995. The Structure, Reactions, Synthesisand Uses, of Heterocyclic Compounds” Katritzky, A. R., Rees, C. W. andScriven, E., F. Ed's Pergamon Press New York, 1996.

Acids or acid chlorides, used for the preparation of compounds useful tothis invention may be commercially available or readily prepared by manymethods known to one skilled in the art of organic chemistry, and aredescribed in “Comprehensive Organic Transformations. A Guide toFunctional Group Preparation.” pp. 385-439. Richard C. Larock 1989 VCHPublishers, Inc. General methods for the synthesis ofimidazo[1,5a]pyrazines, useful for this invention are outlined in thefollowing schemes.

Reductive amination of imidazocarboxaldehyde (A1) with a N-protectedamino alcohol (B1) in the presence of a suitable reducing agent, forexample sodium triacetoxyborohydride, yields compound (C1).Imidazocarboxaldehydes of type (A1) are either commercially available orcan be prepared by methods known in the art. Conversion of the alcoholmoiety in (C1) to the chloride (D1) can be accomplished, for example,using thionyl chloride or by many methods known in the art and aredescribed in Comprehensive Organic Transformations: A Guide toFunctional Group Preparation, pp. 385-439, Richard C. Larock 1989 VCHPublishers, Inc. Cyclization of (D1) to the imidazo[1,5a]pyrazinescaffold (E1) is accomplished using a base, for example triethylamine,in a solvent like dioxane. For examples, where R is a hydrogen,deprotonation of (E1) using a suitable base, for example n-butyllithium,followed by quenching with bromine affords compounds of the type (F1).Suzuki type cross coupling [A. Suzuki et. al., J. Am. Chem. Soc., 1989,111, 513; A. Suzuki, J. Organomet. Chem., 1999, 576, 147; and Zapf,Alexander., Transition Metals for Organic Synthesis (2nd Edition)(2004), 1 211-229] of (F1) with an aryl boronic acid or ester in thepresence of a suitable catalyst such as tetrakis(triphenylphosphine)palladium affords compounds of type (G1). After cross coupling has beenperformed, the product may be deprotected to give the amine intermediate(H1) The choice of protecting group and its method of removal will bereadily apparent to one skilled in the art of organic chemistry. Suchconsiderations and methods are, for example, described by Theodora W.Greene and Peter G. M. Wuts in Protective Groups in Organic Synthesis,3rd Ed. (1999), (John Wiley and Sons, Inc., New York, N.Y. For example,if the protecting group is acetyl, the product may be deprotected bytreatment with aqueous potassium hydroxide at a concentration of 0.5 Nto 5 N at room temperature to 100° C. for a period between 0.5 h and 24h. A method similar to that outlined in Scheme 1 is reported in PCTPublication Number WO 03/076427. Acylation of (H1) using a substitutedbenzoyl chloride in the presence of a base such as triethylamine or asubstituted benzoic acid in the presence of coupling reagents such asEDAC and HOBt affords the compounds of the type (I1).

Treatment of an appropriately substituted chloropyrazine (A2) with abase, for example n-butyllithium, followed by quenching of the resultinganion with dimethylformaldehyde affords the formylpyrazine (B2).Reductive amination of (B2) with an amide (D. Dube et al., Tet. Lett.,1999, 40, 2295-2298) yields the amide (C2). Cyclization of (C2) via theimidoylchloride affords the imidazopyrazine (D2). Imidoylchlorides canbe generated by a variety of methods known in the literature, forexample using thionyl chloride. Reduction of the imidazopyrazine (D2),for example using hydrogen gas in the presence of a metal likepalladium, affords the imidazo[1,5a]pyrazine (E2). Theimidazo[1,5a]pyrazine (E2) can be derivatized into appropriatelyfunctionalized compounds of the type (F2), for example amines, viareductive amination using an aldehyde or ketone and a reducing agent,such as sodium triacetoxyborohydride, or amides via an acid chloride inthe presence of a base such as triethylamine or an acid in the presenceof a coupling agent such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride(BOP-Cl). The imidazo[1,5a]pyrazine (F2) can be further functionalizedat C-4 of the imidazole ring to give compounds of the type (G2). Forexample, bromination of (F2) using bromine followed by displacement ofthe bromine atom with appropriately substituted amines (for example viathe Buchwald-Hartwig protocol, Wolfe, J. P. et. al., J. Org. Chem.,2000, 65, 1158-1174) or with boronic acids via the Suzuki protocol [A.Suzuki et. al., J. Am. Chem. Soc. 1989, 111, 513; A. Suzuki, J.Organomet. Chem., 1999, 147, 576, and Zapf, Alexander., TransitionMetals for Organic Synthesis (2nd Edition) (2004)] affords thecorresponding amino substituted or alkyl/aryl/heteroaryl substituted(G2).

Halogenation of an appropriately substituted methylpyrazine followed bytreatment with an aminating agent and hydrolysis affords the aminosubstituted pyrazine (B3). Halogenation of methylpyrazine can beaccomplished using a variety of halogenating agents, for exampleN-chlorosuccinimide or N-bromosuccinimide. A variety of aminating agentsare commercially available, for example hexamethyltetramine (HMTA) ordi-t-butyl iminodicarboxylate. Coupling of the aminopyrazine (B3) withan appropriately substituted acid chloride in the presence of a base,for example triethylamine, or an acid in the presence of an of acoupling agent, such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride(BOP-Cl) orbenzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate(BOP), affords the amide (C3). The amide (C3) can be processed in asimilar fashion to that outlined for Scheme 2 to afford (G3).

Compounds of the type (E5) can be prepared as outlined in Scheme 5.Enamination of tert-butyl-4-oxopiperidine-1-carboxylate (A5) using anappropriate enamination reagent such as Brederick's reagent[tert-butoxy-bis(dimethylamino) methane] affords the vinylogous amide(B5). Condensation of (B5) with a substituted aryl hydrazine underappropriate conditions (R. Olivera et al., J. Org. Chem., 2000, 65,7010-7019) yields the bicyclic pyrazole (C5). Deprotection of thepiperidine moiety using standard conditions known in the art, forexample anhydrous HCl in dioxane, affords the amine (D5). Acylation of(D5) via a substituted benzoyl chloride in the presence of a base, suchas triethylamine, or a substituted benzoic acid in the presence ofcoupling reagents, such as EDAC and HOBt, affords the compounds of thetype (E5). An alternative route to compounds of the type (E5) can beused whereby 4-piperidone hydrate hydrochloride (F5) is acylated asdescribed above for (D5) to afford (G5). Enamination of (G5) asdescribed above for (A5) provides (H5). Finally, condensation of (H5)with a substituted aryl hydrazine as described above for (B5) affordscompounds of the type (E5).

Compounds of the type (I6) can be prepared similar to the methodsreported in PCT Publication Number WO 03/047520 as outlined in Scheme 6.Condensation of tert-butyl-4-oxopiperidine-1-carboxylate (A6) withmorpholine under dehydrating conditions, such as in the presence ofpara-toluenesulphonic acid, in a solvent, such as toluene, at refluxaffords enamine (B6). Diazotization of a substituted aniline (C6) usingsuitable reagents, such as HCl and sodium nitrite, followed bycondensation of ethylchloroacetoacetate in the presence of a base, suchas sodium acetate, affords the chloroimidate (D6). Condensation of (B6)and (D6) in the presence of a base such as triethylamine in a solventsuch as acetone yields the substituted bicyclic pyrazole (E6).Deprotection of the piperidine moiety using standard conditions known inthe art, for example anhydrous HCl in dioxane, affords the amine (F6).Acylation of (F6) using a substituted benzoyl chloride in the presenceof a base such as triethylamine or a substituted benzoic acid in thepresence of coupling reagents such as EDAC and HOBt affords thecompounds of the type (G6). Finally, hydrolysis under suitableconditions, such as aqueous sodium hydroxide in methanol, to afford (H6)followed by amide bond coupling with an amine using suitable couplingreagents such as EDAC and HOBt affords compounds of the type (16).

Compounds of the type (F7) can be prepared as outlined in Scheme 7.Ethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride can becondensed with formamidine acetate in the presence of a base such assodium methoxide in a solvent such as methanol to afford the bicyclicpyrimidinone (B7). Chlorination under suitable conditions such as in thepresence of POCl₃ affords the chloride (C7). Suzuki type cross coupling[A. Suzuki et. al., J. Am. Chem. Soc., 1989, 111, 513; A. Suzuki, J.Organomet. Chem., 1999, 576, 147; and Zapf, Alexander., TransitionMetals for Organic Synthesis (2nd Edition) (2004), 1 211-229] of (C7)with an aryl boronic acid or ester in the presence of a suitablecatalyst such as tetrakis(triphenylphosphine) palladium affordscompounds of the type (D7). After cross coupling has been performed theproduct is debenzylated. The choice of conditions for debenzylation willbe readily apparent to one skilled in the art of organic chemistry. Suchconsiderations and methods are, for example, described by Greene,Theodora W. and Wuts, Peter G. M. in Protective Groups in OrganicSynthesis, 3rd Ed. (1999) (John Wiley and Sons, Inc., New York, N.Y.). Apreferred method for debenzylation of (D7) uses1-chloroethylchloroformate in the presence of a suitable base such asDIPEA in a suitable solvent such as dichloromethane to afford the amine(E7). Finally, acylation of (E7) using a substituted benzoyl chloride inthe presence of a base, such as triethylamine, or a substituted benzoicacid in the presence of coupling reagents, such as EDAC and HOBt,affords the compounds of the type (F7).

EXAMPLES

The following Examples are offered as illustrative as a partial scope ofthe invention and are not meant to be limiting of the scope of theinvention. Unless otherwise indicated, they have been prepared, isolatedand characterized using the Schemes and other methods disclosed herein.The abbreviations used herein are defined above.

Example 12,4-difluorophenyl(3-(2-(trifluoromethyl)phenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

Step A 2-(4-methoxybenzylamino)ethanol

A 1 L round bottom flask is charged with 2-aminoethanol (29 g, 213mmol), 4-methoxybenzaldehyde (39 g, 639 mmol), methanol (250 mL) andacetic acid (75 mL) under a nitrogen atmosphere. The contents werecooled to 0° C. and sodium triacetoxyborohydride (50 g, 234 mmol) wasadded over a 20 minute period. The reaction mixture was stirred at roomtemperature for 18 hours, concentrated under reduced pressure andpartitioned between water (500 mL) and ethyl acetate (500 mL). The ethylacetate layer was washed with 3N HCl (400 mL). The HCl layer isseparated, cooled to 0° C., made basic using 6N NaOH and extracted withdichloromethane (2×100 mL). The dichloromethane layer was dried oversodium sulfate and concentrated under reduced pressure to yield thetitle compound a as an oil (20 g). ¹H-NMR of the oil was consistent withthe desired structure.

Step B 2-(((1H-imidazol-4-yl)methyl)(4-methoxybenzyl)amino)ethanol

To a heterogeneous mixture of 1H-imidazole-4-carbaldehyde (8.0 g, 83.33mmol) and 2-(4-methoxybenzylamino)ethanol (Step A, 18.1 g, 99.9 mmol) inanhydrous THF (100 mL) was added sodium triacetoxyborohydride (21.2 g,99.9 mmol) over a 15 minute period at room temperature. The reactionmixture was stirred at room temperature for 18 hours, concentrated underreduced pressure and partitioned between saturated aqueous sodiumbicarbonate (200 mL) and dichloromethane (2×200 mL). The dichloromethanelayer was dried over sodium sulfate, concentrated under reduced pressureand purified by silica gel flash chromatography using dichloromethaneand methanol (9:1, 800 mL) followed by dichloromethane:methanol:2.0Mammonia in methanol (850:100:50 mL) to afford the title compound b as anoil (14.5 g), [M+H]⁺ 262.21.

Step CN—((1H-imidazol-4-yl)methyl)-2-chloro-N-(4-methoxybenzyl)ethanamine

To a solution of2-(((1H-imidazol-4-yl)methyl)(4-methoxybenzyl)amino)ethanol (Step B,14.5 g, 55.55 mmol) in anhydrous dioxane (100 mL) was added thionylchloride (16.5 mL, 222.2 mmol) over a 10 minute period. The reactionmixture was heated at 60° C. for 3 hours, cooled to room temperature andpartitioned under reduced pressure. The contents of the flask wereazeotroped with dioxane (2×100 mL) and toluene (2×100 mL). The whitesolid c that separates out is filtered and used as such for thesubsequent step without further purification (19.0 g).

Step D 7-(4-methoxybenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

To N—((1H-imidazol-4-yl)methyl)-2-chloro-N-(4-methoxybenzyl)ethanamine(19.0 g, 53.97 mmol) in anhydrous dioxane (100 mL) was addedtriethylamine (27 mL, 194.3 mmol) over a period of 15 minutes at roomtemperature. The reaction mixture was heated at 90° C. for 6 hours,stirred at room temperature for 18 hours and partitioned between 1N NaOH(75 mL) and ethyl acetate (2×200 mL). The sodium hydroxide layer isreextracted with dichloromethane (100 mL). The ethyl acetate anddichloromethane layers are combined, dried over sodium sulfate,concentrated under reduced pressure and purified by silica gel flashchromatography using dichloromethane and methanol (9.5:0.5, 400 mL) toyield the title compound d (3.9 g), [M+H]⁺ 244.25.

Step E3-bromo-7-(4-methoxybenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

To a solution of 0.2 g (0.82 mmol)7-(4-methoxybenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step D) inanhydrous THF (5 mL), cooled to −78° C. was added n-BuLi (0.36 mL, 0.90mmol, 2.5 M solution in hexane) dropwise over a 15 minute period. Thereaction mixture was stirred at −78° C. for 15 minutes, andcarbontetrabromide (0.3 g, 0.9 mmol) was added dropwise over a 3 minuteperiod. The reaction was stirred at −78° C. for 20 minutes and quenchedby the addition of saturated ammonium chloride (3 mL) at −78° C. Thereaction mixture was bought to room temperature and stirred at roomtemperature for 10 minutes and partitioned between brine (20 mL) anddichloromethane (30 mL). The dichloromethane layer was dried over sodiumsulfate, concentrated under reduced pressure and purified by silica gelflash chromatography using methanol and ethyl acetate (0.5:9.5, 300 mL)to afford the title compound e (0.13 g) as an oil, [M+H]⁺ 324.

Step F7-(4-methoxybenzyl)-3-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

To 0.025 g (0.77 mmol) of3-bromo-7-(4-methoxybenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(Step E) in dioxane (12 mL) and water (4 mL) are sequentially added2-(trifluoromethyl)phenylboronic acid (0.176 g, 0.924 mmol), potassiumcarbonate (0.32 g, 2.31 mmol) andetrakis(triphenylphosphine)palladium(0) (0.089 g, 0.077 mmol) under anitrogen atmosphere. The contents were heated at 100° C. for 20 hours,cooled to room temperature, concentrated under reduced pressure andpartitioned between dichloromethane (50 mL) and brine (20 mL). Thedichloromethane layer was dried over sodium sulfate, concentrated underreduced pressure and purified by silica gel flash chromatography usingdichloromethane/methanol (9.7:0.3, 400 mL) to afford the title compoundf (0.03 g), [M+H]⁺ 388.14.

Step G3-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

To a solution of7-(4-methoxybenzyl)-3-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(Step F, 25 mg) in methanol, at 0° C. and under a nitrogen atmospherewas added palladium hydroxide on carbon (15 mg, 20 wt % Pd-Degussa type,E101) and the contents hydrogenated at 40 psi for 14 hours. The reactionmixture was filtered and the filter cake washed with methanol (2×10 mL).The filtrate was concentrated under reduced pressure and azeotroped withdichloromethane (2×20 mL) and ethyl acetate (2×20 mL). The oil that isobtained g (20 mgs) was used as such for the subsequent step withoutfurther purification.

Step H2,4-difluorophenyl(3-(2-(trifluoromethyl)phenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

To a solution of3-(2-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(20 mgs, 0.07 mmol) in anhydrous DMF (1 mL) and diisopropylethylamine(28 μL, 0.14 mmol) was added 2,4-difluorobenzoyl chloride and thecontents stirred at room temperature for 15 minutes. The reactionmixture was subjected to reverse phase preparative HPLC (YMC S5 20×100mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90%MeOH, 10% H₂O, 0.1% TFA), the desired fractions were collected,concentrated under reduced pressure and partitioned betweendichloromethane (20 mL) and saturated aqueous sodium bicarbonate (10mL). The dichloromethane layer was dried over sodium sulfate andconcentrated under reduced pressure to yield the title compound 1 (4.0mgs), [M+H]⁺ 408.24.

Example 22,4-difluorophenyl(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

Step A 3-chloropyrazine-2-carbaldehyde

A flame dried and cooled 100 mL round bottom flask was charged with2,2,6,6-tetramethylpiperidine (2.5 mL, 14.96 mmol) and anhydrous THF (25mL) under a nitrogen atmosphere. The contents were cooled to −78° C. andn-butyllithium (2.5 M in hexane, 5.7 mL, ˜14.28 mmol) was added dropwiseover a 5 minute period. The reaction mixture was stirred at −78° C. for5 minutes, bought to 0° C. and stirred at 0° C. for 25 minutes. Thereaction mixture was recooled to −78° C. and 2-chloropyrazine (0.78 g, 1mL, 6.8 mmol) was added over a 3 minute period. After 30 minutes at −78°C., anhydrous DMF (0.99 mL, 13.6 mmol) was added over 3 minutes and thecontents stirred at −78° C. for a further 30 minutes. The reactionmixture was bought to 0° C., stirred at 0° C. for 15 minutes, recooledto −78° C. and quenched by the addition of acetic acid (4 mL) in THF (10mL). The reaction mixture was stirred at room temperature for 10 minutesand partitioned between ethyl acetate (60 mL) and brine (30 mL). Theethyl acetate layer is separated, dried over sodium sulfate,concentrated under reduced pressure and purified by silica gel flashchromatography using dichloromethane and ethyl acetate (9.5:0.5, 400 mL)to yield the title compound a (950 mg). ¹H-NMR of the compound wasconsistent with the desired structure.

Step B N-((3-chloropyrazin-2-yl)methyl)-2,4-difluorobenzamide

To 3-chloropyrazine-2-carbaldehyde (Step A, 0.95 g, 6.69 mmol) intoluene (20 mL) were sequentially added triethylsilane (3.3 mL, 20.07mmol) and TFA (1.52 mL, 20.07 mmol) at room temperature. The reactionmixture was heated at 80° C. for 3.5 hours, cooled to room temperatureand concentrated under reduced pressure. Ethyl acetate (20 mL) was addedand the solid that separates out was filtered. The filtrate wasconcentrated under reduced pressure and purified by silica gel flashchromatography using dichloromethane and ethyl acetate (9:0.5, 300 mL to9:1, 400 mL). The desired fractions were collected, concentrated underreduced pressure and used as b for the subsequent step.

Step C 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine

To N-((3-chloropyrazin-2-yl)methyl)-2,4-difluorobenzamide (Step B, 1.15g, 4.05 mmol) in toluene (20 mL) were sequentially added phosphorylchloride (0.5 mL, 5.26 mmol) and diisopropylethylamine (1.05 mL, 5.67mmol) and the contents heated at 120° C. for 6 hours. The reactionmixture is cooled to room temperature, and phosphoryl chloride (1 mL)and diisopropylethylamine (2 mL) are added and the contents heated at120° C. for an additional 4 hours. The reaction mixture was stirred atroom temperature for 3½ days, concentrated under reduced pressure andpartitioned between ethyl acetate (100 mL) and water (50 mL). The ethylacetate layer was washed with saturated aqueous sodium bicarbonate (30mL) and water (30 mL), dried over sodium sulfate and concentrated underreduced pressure. To the residue that is obtained was added 60 mL ofhexane/ethyl acetate mixture (3.5:1.5). The solid that was obtained isfiltered. The filtrate was concentrated under reduced pressure andpurified by silica gel flash chromatography using hexane/ethyl acetate(3.5:1.5, 400 mL to 3:2, 300 mL). The desired fractions were isolatedand concentrated under reduced pressure to yield the title compound c asa solid (240 mgs), [M+H]⁺ 266.16.

Step D 3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine

To a solution of 8-chloro-3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine(Step C, 200 mg) in methanol, at 0° C. and under a nitrogen atmospherewas added palladium on carbon (75 mgs, 10 wt % Pd) and the contentshydrogenated at 50 psi for 20 hours. The reaction mixture was filteredand the filter cake washed with methanol (2×10 mL). The filtrate wasconcentrated under reduced pressure to yield a solid d (175 mgs) thatwas used as such for the subsequent step without further purification.

Step E2,4-difluorophenyl(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

This compound 2 was prepared as described for Example 1 (Step H)starting from 50 mg of3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step D)and 2,4-difluorobenzoyl chloride. Yield: 14 mgs, [M+H]⁺ 376.18.

Example 3(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone

To 3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine(Example 2, Step D, 0.29 g, 1.23 mmol) in anhydrous DMF (3 mL) weresequentially added 6-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid(WO 04/032874, 0.237 g, 1.23 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate(1.1 g, 2.46 mmol) and triethylamine (0.51 mL, 3.69 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 70hours and partitioned between ethyl acetate (75 mL) and saturatedaqueous sodium bicarbonate (30 mL). The ethyl acetate layer was washedwith 10% lithium chloride solution (2×30 mL), dried over sodium sulfateand purified by silica gel flash chromatography using dichloromethaneand methanol (9.5:0.5, 400 mL) to yield the title compound 3 (0.5 g),[M+H]⁺ 410.25.

Example 42-(5-(3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl-2-oxoacetamide

To a solution of(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Example 3, 0.09 g, 0.22 mmol) in dichloromethane (2 mL) and cooled to0° C., was added oxalyl chloride (58 μL, 0.66 mmol) over a 3 minuteperiod. The reaction mixture was stirred at room temperature for 45minutes, concentrated under reduced pressure, and dimethylamine (2.0M inTHF, 0.66 mL, 1.32 mmol) was added over a period of 3 minutes at roomtemperature. The reaction mixture was stirred at room temperature for 18hours and partitioned between dichloromethane (20 mL) and saturatedaqueous sodium bicarbonate (10 mL). The dichloromethane layer isseparated, dried over sodium sulfate, concentrated under reducedpressure and subjected to reverse phase preparative HPLC (YMC S5 20×100mm, 10 min. run, solvent A: 10% MeOH: 90% H₂O: 0.1% TFA, solvent B: 90%MeOH, 10% H₂O, 0.1% TFA). The desired fractions were collected,concentrated under reduced pressure and partitioned betweendichloromethane (20 mL) and saturated aqueous sodium bicarbonate (10mL). The dichloromethane layer was dried over sodium sulfate andconcentrated under reduced pressure to yield the title compound 4 (1.4mg), [M+H]⁺ 509.01.

Example 5(6-chloro-1-methyl-1H-indol-5-yl)(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

Step A Di-tert-butylimino(pyrazin-2-ylmethyl)carbamate

To a solution of 2-(chloromethyl)pyrazine (Synthesis, 1984, 676-679, 26g, 48% pure) in DMF (260 mL) was added anhydrous potassium carbonate(41.6 g) and di-t-butyl iminodicarboxylate (26 g). The reaction mixturewas heated at 85° C. for 4 h, concentrated under reduced pressure andpartitioned between ethyl acetate and water. The ethyl acetate layer wasseparated, dried over sodium sulfate, concentrated under reducedpressure and purified by silica gel flash chromatography using petroleumether: ethyl acetate (5% to 20%) to afford the title compound a as asolid (27 g). ¹H NMR (400 MHz) (CDCl₃) δ 1.49 (s, 18H), 4.98 (2H), 8.47(d, J=4 Hz, 1H), 8.52 (2H).

Step B Pyrazin-2-ylmethanamine dihydrochloride

Di-tert-butylimino(pyrazin-2-ylmethyl)carbamate (Step A, 20 g, 6.51mmol) was dissolved in ethyl acetate (100 mL), and a solution of HCl inethyl acetate (2 N, 100 mL) was added at room temperature. After 3 h,the reaction mixture was filtered, washed with ethyl acetate under a N₂atmosphere and dried to yield the title compound b as a hygroscopicsolid (9.7 g), [M+H]⁺ 110.

Alternate Method

An alternate approach to the title compound b involves the reaction of2-(chloromethyl)pyrazine with hexamethylenetetramine followed byhydrolysis of the salt with concentrated hydrochloric acid in ethanol(as shown in scheme 3)

Step C 2,4-difluoro-N-(pyrazin-2-ylmethyl)benzamide

To pyrazin-2-ylmethanamine dihydrochloride (Step B, 18.0 g, 98.9 mmol)was added dioxane (180 mL) followed by disopropylethylamine (40.4 g, 316mmol) and the mixture stirred at room temperature for 0.25 hours.2,4-Difluorobenzoyl chloride (21.45 g, 118.68 mmol) was added dropwiseat 0° C. The reaction mixture was stirred at room temperature overnight,concentrated under reduced pressure and partitioned between ethylacetate and aq. NaOH solution. The ethyl acetate layer was washed withbrine, dried over sodium sulfate concentrated under reduced pressure andpurified by silica gel flash chromatography using petroleum ether: ethylacetate system (5% to 40%) to afford the title compound c as a solid.(14.0 g), [M+H]⁺ 249.9.

Step D 3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine

To a suspension of 2,4-difluoro-N-(pyrazin-2-ylmethyl)benzamide (Step C,13.0 g, 52.2 mmol) in dry toluene (140 mL) was added distilledphosphoryl chloride (10.4 mL) dropwise at 0° C. The reaction mixture wasrefluxed for 2.5 hours, concentrated under reduced pressure andpartitioned between ethyl acetate and water. The ethyl acetate layer iswashed with saturated aqueous sodium bicarbonate and brine, dried oversodium sulfate, concentrated under reduced pressure and purified bysilica gel flash chromatography using chloroform:methanol system (0% to1% of methanol). The desired fractions collected and concentrated underreduced pressure to afford the title compound d as a solid. (Yield 4.5g), [M+H]⁺ 231.9.

Step E 3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazineAlso See Example 2, Step D

3-(2,4-difluorophenyl)imidazo[1,5-a]pyrazine (Step D, 5.0 g) wasdissolved in methanol (50 mL), and 10% palladium hydroxide (2.0 g) wasadded under N₂ atmosphere. The contents were hydrogenated at 5 kg/cm⁻²pressure over night, concentrated under reduced pressure and purified bysilica gel flash chromatography using chloroform:methanol (0% to 9% ofmethanol). The desired fractions were collected, concentrated underreduced pressure and redissolved in a mixture of ethyl acetate andhydrochloric acid in dioxane. The solid that precipitates out wasfiltered and triturated repeatedly with ethyl acetate. The hydrochloricacid salt was dissolved in sat. bicarbonate solution and extracted inethyl acetate. The ethyl acetate layer was dried over sodium sulfate andconcentrated to afford the title compound e (1.9 g), [M+H]⁺ 235.9.

Step F(6-chloro-1H-indol-5-yl)(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone

This compound was prepared in a similar fashion to that outlined inExample 3, starting from3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Step F,0.1 g) and 6-chloro-1-methyl-1H-indole-5-carboxylic acid (WO 04/022712)to yield the title compound 5 (0.15 g), [M+H]⁺ 427.09.

Example 62-(6-chloro-5-(3-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

This compound was prepared in a similar fashion to that outlined inExample 4 starting from(6-chloro-1H-indol-5-yl)(3-(2,4-difluorophenyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone(Example 5, 0.15 g) to afford the title compound 6 as a solid (0.093 g),[M+H]⁺ 526.12.

Examples 7 to 41

Compounds listed in Tables 1 and 2 were prepared using methods describedin Examples 1 to 6.

TABLE 1

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺     7(±)¹

1.39 (A) 551.17    8(±)

1.98 (B) 565.34  9

1.99 (A) 423.39 10

1.64 (A) 522.34 11

1.78 (A) 512.36 12

1.85 (A) 408.24 13

2.63 (C) 432.27 14

1.50 (C) 391.31 15

1.46 (C) 424.24 16

1.41 (C) 375.28 17

2.15 (C) 410.18 18

2.02 (C) 368.28 19

1.96 (C) 392.20 20

1.70 (C) 360.24 21

2.38 (C) 397.20 22

2.21 (C) 380.22 23

2.28 (C) 442.11 24

2.48 (C) 394.24 25

2.07 (C) 390.24 26

1.90 (C) 384.26 27

2.04 (C) 391.24 28

1.64 (C) 376.26 ¹(±)denotes a racemic compound. *(A): YMC S5 CombiscreenODS; 4.6 × 50 mm (4 min. gradient); Solvent A = 10% MeOH, 90% H₂O, 0.2%H₃PO₄; solvent B = 90% MeOH, 10% H₂O, 0.2% H₃PO₄. (B): YMC C18 S; 4.6 ×50 mm (4 min. gradient); Solvent A = 10% MeOH, 90% H₂O, 0.2% H₃PO₄;solvent B = 90% MeOH, 10% H₂O, 0.2% H₃PO₄. (C): Waters SunFire C18, 4.6× 50 mm × 5 μM; Solvent A = 10% MeOH, 90% H₂O, 0.1% TFA; solvent B = 90%MeOH, 10% H₂O, 0.1% TFA.

TABLE 2 HPLC ret. Ex. Time, min. No. Structure (column conditions)* [M +H]⁺ 29(±)

1.6  384.28 30(±)

1.89 416.26 31   

1.74 402.14 *(A): YMC S5 Combiscreen ODS; 4.6 × 50 mm (4 min. gradient);Solvent A = 10% MeOH, 90% H₂O, 0.2% H₃PO₄; solvent B = 90% MeOH, 10%H₂O, 0.2% H₃PO₄.

Example 322,6-Difluorophenyl(1-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-methanone

Step A Tert-butyl3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate

To tert-butoxy bis(dimethylamino)methane (20.8 mL) was added tert-butyl4-oxopiperidine-1-carboxylate (20.0 g) and the resulting mixture washeated at 110° C. for 16 h. After cooling to rt, the mixture waspurified by flash chromatography on silica gel using a gradient elutionof 5% methanol in methylene chloride to 10% methanol in methylenechloride. Concentration of the combined fractions containing the majorproduct afforded the desired product a (11.8 g) as a dark orange oilwhich was used in the next step without any further purification.

Step B Tert-butyl1-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate(Step A, 2.1 g, 8.3 mmol) was dissolved in 100 mL methanol, and water(50 mL) was added followed by the addition of sodium carbonate (0.53 g,5.0 mmol) and phenyl hydrazine hydrochloride (1.43 g, 9.9 mmol).Finally, acetic acid (1 mL) was added and the resulting mixture wasstirred at rt for 1 h. The mixture was made basic by adding saturatedaq. sodium bicarbonate (ca. 20 mL) and the methanol was removed on arotary evaporator. The resulting mixture was extracted with methylenechloride (3×40 mL) and the combined extracts were dried over anhyd.sodium sulfate, filtered, and concentrated to afford the crude product.Purification by flash chromatography on silica gel using 20% ethylacetate in hexanes as the eluant afforded fractions containing thedesired product. Concentration of the combined fractions afforded thedesired product b as a yellow oil (1.63 g, 66%). ¹H NMR (400 MHz,d³-MeOD): δ 7.73 (s, 1H), 7.60-7.47 (m, 5H), 4.37 (s, 2H), 3.57 (t,J=6.1 Hz, 2H), 3.17 (t, J=6.0 Hz, 2H).

Step C 1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinehydrochloride

Tert-butyl1-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (StepB, 1.6 g, 5.4 mmol) was dissolved in anhyd dioxane (10 mL) and 4 N anhydHCl in dioxane (10 mL) was added. After heating the resulting solutionat 40° C. for 1.5 h, the mixture was cooled to rt and the precipitatedsolid was collected by vacuum filtration and rinsed with additionaldioxane (10 mL). The resulting hygroscopic solid was then dissolved inmethanol (˜75 mL) and reconcentrated to initially yield a oil whichfoamed and solidified under vacuum to provide the desired product c as alight tan colored solid (1.45 g, ˜100%). ¹H NMR (400 MHz, d³-MeOD): δ7.55 (s, 1H), 7.53-7.50 (m, 4H), 7.48 (m, 1H), 4.52 (s, 2H), 3.70 (t,J=5.7 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.51 (s, 9H).

Step D2,6-difluorophenyl(1-phenyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)methanone

To a slurry of 1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinehydrochloride (Step C, 50 mg, 0.18 mmol) in methylene chloride (0.5 mL)were successively added diisopropylethylamine (0.07 mL, 0.41 mmol) and2,6-difluorobenzoyl chloride. After stirring at rt for 30 min, themixture was partitioned between methylene chloride (5 mL) and water (1mL). The organic layer was collected and concentrated in vacuo to affordan oil which was purified by reverse-phase preparative HPLC (YMC S520×100 mm, 10 min. run, solvent A: 10% MeOH, 90% H₂O, 0.1% TFA; solventB: 90% MeOH, 10% H₂O, 0.1% TFA). Fractions containing the major productwere collected and concentrated on a rotary evaporator to remove themethanol followed by lyophilization of the remaining aqueous solution toafford the desired product 32 as a pale yellow semi-solid (33 mg, 53%).HPLC Ret. time=2.83 min (HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mmcolumn with a binary solvent system where solvent A=10% methanol, 90%water, 0.2% phosphoric acid and solvent B=90% methanol, 10% water, and0.2% phosphoric acid, flow rate=4 mL/min, linear gradient time=4 min,start % B=0, final % B=100), LCMS [M+H]⁺ 340.1.

Examples 33 to 37

Compounds listed in Table 3 were prepared using methods described inExample 32.

TABLE 3

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺ 33

2.88 304.17 34

2.89 322.13 35

2.95 322.14 36

3.02 318.17 37

2.90 343.17 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water and 0.2%phosphoric acid, and solvent B = 90% methanol, 10% water and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

Example 38(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(2,6-difluorophenyl)methanone

Step A Tert-butyl1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate

Tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate(Example 32, Step A, 2.0 g) was reacted with 2-chlorophenyl hydrazinehydrochloride as described for Example 32, Step B to yield the titlecompound a as a yellow oil (1.39 g, 53%). ¹H NMR (400 MHz, CDCl₃): δ7.56-7.54 (m, 2H), 7.45-7.40 (m, 3H), 4.54 (s, 2H), 3.72 (br s, 2H),2.58 (br s, 2H), 1.51 (s, 9H).

Step B 1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

Tert-butyl1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(Step A, 0.65 g) was prepared as described for Example 32, Step C toyield the title compound b as a pale yellow solid (0.55 g, 92%). ¹H NMR(400 MHz, d³-MeOD): δ 7.74 (s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.62-7.50(m, 3H), 4.38 (s, 2H), 3.58-3.55 (m, 2H), 2.92-2.89 (m, 2H).

Step C(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(2,6-difluorophenyl)methanone

1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (StepB, 50 mg) was reacted with 2,6-difluorobenzoyl chloride as described forExample 32, Step D to afford the crude product, which was purified byreverse-phase preparative (YMC S5 20×100 mm, 10 min. run, solvent A: 10%MeOH, 90% H₂O, 0.1% TFA; solvent B: 90% MeOH, 10% H₂O, 0.1% TFA).Fractions containing the major product were collected and neutralized byadding satd aq. sodium barcarbonate (˜1 mL) and concentrated on a rotaryevaporator to remove the methanol. The resulting aqueous slurry wasfiltered to collect the solid. The solid was washed and rinsed withadditional water (˜1 mL) and dried under vacuum to afford the titlecompound 38 as a white solid (35 mg, 54%). HPLC Ret. Time=2.82 min (HPLCconditions: Ballistic YMC S5 ODS 4.6×50 mm column with a binary solventsystem where solvent A=10% methanol, 90% water, 0.2% phosphoric acid andsolvent B=90% methanol, 10% water, and 0.2% phosphoric acid, flow rate=4mL/min, linear gradient time=4 min, start % B=0, final % B=100). LCMS[M+H]⁺ 374.10.

Example 39(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(2,6-dichlorophenyl)methanone

1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(Example 38, Step B, 50 mg) was reacted with 2,6-difluorobenzoylchloride as described for Example 38 to afford the title compound 39 asan off-white solid (42 mg, 62%). HPLC Ret. Time=2.99 and 3.07 min (1:1mixture of apparent atropisomers) (HPLC conditions: Ballistic YMC S5 ODS4.6×50 mm column with a binary solvent system where solvent A=10%methanol, 90% water, 0.2% phosphoric acid and solvent B=90% methanol,10% water, and 0.2% phosphoric acid, flow rate=4 mL/min, linear gradienttime=4 min, start % B=0, final % B=100). LCMS [M+H]⁺ 406.02.

Example 40(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(1H-indol-5-yl)methanone

1H-indole-5-carboxylic acid (63 mg, 0.39 mmol), EDAC (82 mg, 0.43 mmol)and HOBt (58 mg, 0.43 mmol) were dissolved in DMF (1 mL) and theresulting solution was stirred at rt for 1 h. At this time,1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(Example 38, Step B, 100 mg, 0.33 mmol) and DIPEA (0.18 mL, 1.0 mmol)were successively added and the mixture was heated at 60° C. for 3 h.After cooling to rt, water (˜20 mL) was added and the mixture wasextracted with ethyl acetate (3×10 mL). The combined extracts werewashed with brine and concentrated and the resulting material waspurified by flash chromatography on silica gel using 70-80% ethylacetate in hexanes mixture as the eluant. Fractions containing the majorproduct were combined and concentrated under vacuum to afford the titlecompound 40 as a white solid (104 mg, 84%). HPLC Ret. Time=2.88 min(HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mm column with a binarysolvent system where solvent A=10% methanol, 90% water, 0.2% phosphoricacid and solvent B=90% methanol, 10% water, and 0.2% phosphoric acid,flow rate=4 mL/min, linear gradient time=4 min, start % B=0, final %B=100). LCMS [M+H]⁺ 377.14.

Examples 41 to 50

Compounds listed in Table 4 were prepared using methods described inExample 40.

TABLE 4

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺ 41

3.27 377.12 42

2.80 377.12 43

3.07 377.12 44

3.01 377.12 45

2.98 378.11 46

3.06 378.11 47

1.83 378.10 48

3.08 391.05 49

3.16 391.06 50

3.20 377.06 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

Example 512-(5-(1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

To a solution of(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(1H-indol-5-yl)methanone(Example 40, 83 mg, 0.22 mmol) in methylene chloride (2 mL) at 0° C. wasadded a 2 M solution of oxalyl chloride (0.13 mL, 0.26 mmol) and theresulting mixture was stirred at 0° C. for 15 min, then allowed to warmto rt and stirred for an additional 1.5 h. The mixture was concentratedand the resulting residue was slurried in methylene chloride (1 mL) anda 2 M solution of dimethylamine in THF (0.3 mL) was added. Afterstirring at rt for 15 min, the clear solution was concentrated and theresidue was purified by reverse phase preparative HPLC (HPLC conditions:YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH, 90% H₂O, 0.1% TFA;solvent B: 90% MeOH, 10% H₂O, 0.1% TFA). Fractions containing thedesired product were collected and concentrated to remove the methanol,and satd. aq. sodium bicarbonate (1 mL) was added. The mixture wasextracted with ethyl acetate (3×5 mL) and the combined extracts werewashed with brine, dried over anhyd.sodium sulfate and concentrated toafford the title compound 51 as a tan colored solid (33 mg, 31%). HPLCRet. Time=2.55 min (HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mmcolumn with a binary solvent system where solvent A=10% methanol, 90%water, 0.2% phosphoric acid and solvent B=90% methanol, 10% water, and0.2% phosphoric acid, flow rate=4 mL/min, linear gradient time=4 min,start % B=0, final % B=100). LCMS [M+H]⁺ 476.14.

Examples 52-53(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)methanone

Step A Example 53 Tert-butyl6-(1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate

2-(tert-butoxycarbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carboxylicacid (WO 2000/059904, 60 mg, 0.19 mmol) was coupled to1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(Example 38, Step B, 53 mg, 0.17 mmol) as described for Example 40 toafford the title compound 53 as a light tan colored solid (95 mg, 94%).LCMS [M+H]⁺ 532.18.

Step B(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-yl)methanone

To a solution of tert-butyl6-(1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(Step A, 95 mg, 0.18 mmol) in dioxane (1 mL) was added a 4 N solution ofanhyd. HCl in dioxane (0.5 mL). After stirring at rt for 30 min, hexane(1 mL) was added and the precipitated solid was collected by vacuumfiltration. The resulting hygroscopic solid was purified by reversephase preparative HPLC (HPLC conditions: YMC S5 20×100 mm, 10 min. run,solvent A: 10% MeOH, 90% H₂O, 0.1% TFA; solvent B: 90% MeOH, 10% H₂O,0.1% TFA). Fractions containing the desired product were collected andconcentrated to remove the methanol and the remaining aqueous portionwas neutralized by the addition of satd. aq. sodium bicarbonate. Theresulting solid was collected by vacuum filtration and dried undervacuum to afford the title compound 52 as a cream colored solid (41 mg,53%).

HPLC Ret. Time=2.08 min (HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mmcolumn with a binary solvent system where solvent A=10% methanol, 90%water, 0.2% phosphoric acid and solvent B=90% methanol, 10% water, and0.2% phosphoric acid, flow rate=4 mL/min, linear gradient time=4 min,start % B=0, final % B=100). LCMS [M+H]⁺ 432.13.

Example 54(6-chloro-1-methyl-1H-indol-5-yl)(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)methanone

6-chloro-1-methyl-1H-indole-5-carboxylic acid (WO 04/022712) was coupledto 1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(Example 38, Step B) as described in Example 40 to afford the titlecompound 54 as clear oil (2 mg). HPLC Ret. Time=3.24 min. (HPLCconditions: YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); SolventA=10% MeOH, 90% H₂O, 0.2% H₃PO₄; solvent B=90% MeOH, 10% H₂O, 0.2%H₃PO₄). LCMS [M+H]⁺ 425.03.

Example 552-(6-chloro-5-(1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-1-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

The title compound 55 was prepared from(6-chloro-1-methyl-1H-indol-5-yl)(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)methanone(Example 54) as described in Example 51 to afford the title compound 55as a white solid (2 mg). HPLC Ret. Time=2.80 min. (HPLC conditions: YMCS5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄). LCMS [M+H]⁺524.08.

Example 56(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone

6-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (PCT PublicationNumber WO 04/032874) was coupled to1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(Example 38, Step B) as described in Example 40 to afford the titlecompound 56 as a white solid. HPLC Ret. Time=2.80 min (HPLC conditions:Ballistic YMC S5 ODS 4.6×50 mm column with a binary solvent system wheresolvent A=10% methanol, 90% water, 0.2% phosphoric acid and solventB=90% methanol, 10% water, and 0.2% phosphoric acid, flow rate=4 mL/min,linear gradient time=4 min, start % B=0, final % B=100). LCMS [M+H]⁺408.15.

Example 572-(5-(1-(2-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethyl-2-oxoacetamide

The title compound 57 was prepared from(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(6-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone(Example 56, 30 mg) as described in Example 51 to afford the titlecompound 57 as a white solid (13.8 mg, 37%). HPLC Ret. Time=2.60 min(HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mm column with a binarysolvent system where solvent A=10% methanol, 90% water, 0.2% phosphoricacid and solvent B=90% methanol, 10% water, and 0.2% phosphoric acid,flow rate=4 mL/min, linear gradient time=4 min, start % B=0, final %B=100). LCMS [M+H]⁺ 507.30.

Examples 58 to 60

Compounds listed in Table 5 were prepared as in Example 57 using themethods described in Example 57.

TABLE 5

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺ 58

2.82 533.32 59

2.61 479.28 60

2.53 549.35 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

Example 61(1-(2-chlorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)methanone

To a solution of(1-(2-chlorophenyl)-6,7-dihydro-1H-pyazolo[4,3-c]pyridin-5(4H)-yl)(1H-indol-5-yl)methanone(Example 40, 40 mg, 0.11 mmol) in DMF (0.3 mL) at rt was added sodiumhydride (60% dispersion, 25 mg, 0.64 mmol) and the resulting mixture wasstirred at rt for 15 min., then 2-chloro-N,N-dimethylethylaminehydrochloride (36 mg, 0.21 mmol) was added and the mixture was stirredat rt for 16 h. The resulting reaction mixture was directly subjected topurification by reverse phase preparative HPLC (HPLC conditions: YMC S520×100 mm, 10 min. run, solvent A: 10% MeOH, 90% H₂O, 0.1% TFA; solventB: 90% MeOH, 10% H₂O, 0.1% TFA). Fractions containing the desiredproduct were collected and concentrated to remove the methanol and theremaining aqueous portion was lyophilized to afford the trifluoroaceticacid salt of the title compound 61 as an off-white solid (40 mg, 64%).HPLC Ret. Time=2.23 min (HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mmcolumn with a binary solvent system where solvent A=10% methanol, 90%water, 0.2% phosphoric acid and solvent B=90% methanol, 10% water, and0.2% phosphoric acid, flow rate=4 mL/min, linear gradient time=4 min,start % B=0, final % B=100). LCMS [M+H]⁺ 476.24.

Examples 62 to 66

Compounds listed in Table 6 were prepared using the methods described inExample 61.

TABLE 6

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺ 62

3.07 391.13 63

3.41 419.12 64

2.16 448.19 65

2.19 490.20 66

2.28 462.24 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

Example 672,6-difluorophenyl(1-(2,4-difluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)methanone

Step A 1-(2,6-difluorobenzoyl)piperidin-4-one

To a solution of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5mmol) in methylene chloride (32 mL) at rt were successively added DIPEA(1.4 mL, 7.8 mmol) and 2,6-difluorobenzoyl chloride (0.82 mL, 6.5 mmol).The resulting heterogeneous mixture was stirred at rt for 2 d. Theresulting mixture was washed with 1 N aq. sodium hydroxide (3×10 mL) andthe combined basic aqueous portion was back-extracted with methylenechloride (2×10 mL). The organic extracts were combined and washed with10% aq. citric acid (2×10 mL), brine (20 mL), and dried over anhydsodium sulfate. Concentration under vacuum afforded the title compound aas a pale yellow solid (1.29 g, 83%). ¹H NMR (400 MHz, d³-MeOD): δ 7.60(m, 1H), 7.18-7.09 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.3 Hz,2H), 2.62 (t, J=6.4 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H).

Step B1-(2,6-difluorobenzoyl)-3-((dimethylamino)methylene)piperidin-4-one

A mixture of 1-(2,6-difluorobenzoyl)piperidin-4-one (Step A, 0.94 g, 3.9mmol) and tert-butoxy bis(dimethylamino)methane (0.86 mL, 3.9 mmol) washeated at 110° C. for 3 h then cooled to rt. Purification of theresulting mixture by flash chromatography on silica gel initiallyeluting with 100% ethyl acetate then finally eluting with 5% methanol inethyl acetate afforded fractions containing the desired product.Concentration of these fractions afforded the title compound b as a paleyellow solid (1.09 g, 60%). LCMS [M+H]⁺ 295.1.

Step C2,6-difluorophenyl(1-(2,4-difluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)methanone

To 1-(2,6-difluorobenzoyl)-3-((dimethylamino)methylene)piperidin-4-one(Step B, 0.10 g, 0.34 mmol) was reacted with 2,4-difluorophenylhydrazine hydrochloride as described in Example 32, Step B, to yield thetitle compound 67 as a white solid (36 mg, 28%). HPLC Ret. time=2.81 min(HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mm column with a binarysolvent system where solvent A=10% methanol, 90% water, 0.2% phosphoricacid and solvent B=90% methanol, 10% water, and 0.2% phosphoric acid,flow rate=4 mL/min, linear gradient time=4 min, start % B=0, final %B=100). LCMS [M+H]⁺ 376.18.

Examples 68 to 73

Compounds listed in Table 7 were prepared using methods described inExample 67.

TABLE 7

HPLC ret. Ex. Time, min. No. G (column conditions)* [M + H]⁺ 68

2.92 392.09 69

2.74 358.13 70

3.19 374.12 71

2.81 376.14 72

2.88 354.15 73

3.28 408.11 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100

Examples 74-761-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

Step A Tert-butyl 4-morpholino-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl-4-oxo-1-piperidine carboxylate (8.0 g, 40mmol) and morpholine (3.6 g, 42 mmol) in benzene (16 mL) was addedp-toluenesulfonic acid (40 mg) and the resulting solution was refluxedusing a Dean-Stark trap for 24 h. After cooling to rt, the solution wasconcentrated under vacuum to afford the title compound a as a thickreddish-orange oil which was used without any further purification (11.1g, ˜quant). ¹H NMR (400 MHz, CDCl₃): δ 7.36 (s, 1H), 3.94 (br s, 2H),3.74 (m, 4H), 3.54 (m, 2H), 2.80 (m, 4H), 2.16 (br s, 2H), 1.47 (s, 9H).

Step B Ethyl 2-chloro-2-(2-(2-chloro-4-fluorophenyl)hydrazono)acetate

To a slurry of 2-chloro-4-fluoroaniline (5.0 g, 34.3 mmol) in water (20mL) was added conc. HCl (9.5 mL) and the slurry was cooled in an icebath. To this mixture was then added dropwise a mixture of sodiumnitrite (2.43 g, 35.3 mmol) in water (20 mL) over ˜20 min and themixture was stirred at 0° C. for an additional 1 h. The resultingsolution was then added to a mixture of ethyl-2-chloroacetoacetate (4.6mL, 33.3 mmol) and sodium acetate (6.28 g, 76.6 mmol) in acetone (50 mL)at rt followed by stirring at rt for 16 h. The resulting heterogeneousmixture was briefly sonicated to give a uniform suspension and themixture was diluted with water (150 mL) and stirred vigorously for 1 h.The solid was collected by vacuum filtration, rinsed with additionalwater (3×100 mL portions) and dried under vacuum to afford the titlecompound b as a yellow solid (8.7 g, 94%). ¹H NMR (400 MHz, CDCl₃): δ8.69 (s, 1H), 7.61-7.58 (m, 1H), 7.13-7.11 (m, 1H), 7.05-7.00 (m, 1H),4.40 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H).

Step C 5-tert-butyl 3-ethyl1-(2-chloro-4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate

To a solution of tert-butyl4-morpholino-5,6-dihydropyridine-1(2H)-carboxylate (Step A, 9.3 g, 31.3mmol) in ethyl acetate (70 mL) at rt were successively addedtriethylamine (8.7 mL) and ethyl2-chloro-2-(2-(2-chloro-4-fluorophenyl)-hydrazono)acetate (Step B, 8.7g, 31.3 mmol) and the resulting solution was stirred at rt for 16 h. Themixture was filtered to remove the solids and the resulting clearfiltrate was washed with water (3×60 mL), and brine (50 mL), then driedover anhyd.sodium sulfate. Concentration under vacuum afforded a darkred oil which was redissolved in diethyl ether and reconcentrated undervacuum to initially afford an oil which solidified upon drying undervacuum to provide 16.5 g of an orange solid. This material was dissolvedin ethanol (100 mL), and 20% aq HCl (10 mL) was added followed bystirring at rt for 1 h. Saturated aq. sodium bicarbonate was then slowlyadded and the mixture was stirred vigorously for 2 h. The precipitatedsolid was collected by vacuum filtration, rinsed with water andair-dried in funnel to afford the title compound c as a yellow solid(10.68 g, 81%). LCMS [M+H]⁺ 424.63.

Step D Ethyl1-(2-chloro-4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylatehydrochloride

To a solution of 5-tert-butyl 3-ethyl1-(2-chloro-4-fluorophenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-3,5(4H)-dicarboxylate(Step C, 10.68 g, 25.2 mmol) in anhyd.dioxane (110 mL) at rt was added 4N anhyd.HCl in dioxane (20 mL) and the resulting mixture was stirred at50° C. for 3 h. At this time, hexane (125 mL) was slowly added and theprecipitated solid was collected by vacuum filtration and dried undervacuum to provide the title compound d as a light tan-colored solid(8.23 g, 91%). LCMS [M+H]⁺ 324.06.

Step E Example 75 Ethyl1-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate

A mixture of 1H-indole-3-carboxylic acid (0.99 g, 6.13 mmol), EDAC (1.28g, 6.68 mmol) and HOBt (0.83 g, 6.13 mmol) in DMF (6 mL) was stirred atrt for 2.5 h and the resulting slurry was transferred into a slurry ofethyl1-(2-chloro-4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylatehydrochloride (Step D, 2.0 g, 5.57 mmol) and DIPEA (2.3 mL) in DMF (6mL) at rt. After stirring for 1 h, the resulting mixture was slowlyadded with stirring to a mixture of satd. aq sodium bicarbonate (˜25 mL)and water (100 mL). The solid was collected by vacuum filtration andpartially air-dried in the funnel. The solid was then dissolved in ethylacetate (˜150 mL), washed with brine, dried over anhyd sodium sulfate,filtered and concentrated under vacuum to afford the title compound 75as an off-white solid (2.53 g, 98%).

Step F Example 761-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid

To a slurry of ethyl1-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylate(Step E, 2.45 g, 5.3 mmol) in methanol (30 mL) at rt was added 3 N aqsodium hydroxide (6 mL) and the resulting slurry was heated to 55° C.and stirred for 1.5 h. The clear solution was concentrated under vacuumto remove the methanol and the resulting solids were dissolved in water(100 mL) and the aqueous solution was made acidic to pH ˜1 by slowlyadding 1 N aq HCl. The precipitated solid was collected by vacuumfiltration and dried overnight to afford the title compound 76 as anoff-white solid (2.23 g, 97%). LCMS [M+H]⁺ 439.53.

Step G1-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

A mixture of1-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Step F, 40 mg, 0.09 mmol), EDAC (21 mg, 0.11 mmol) and HOBt (14mg, 0.10 mmol) in DMF (0.25 mL) was stirred at rt for 2.5 h. To thismixture was then added ammonia as a 20% solution in methanol (0.030 mL)followed by stirring at rt for 16 h. Water was added (˜4 mL) followed bythe addition of saturated aq. sodium bicarbonate (˜1 mL), and theprecipitated solid was collected by vacuum filtration and rinsed withwater (˜5 mL) and dried to afford the title compound 74 as an off-whitesolid (35 mg, 87%) LCMS [M+H]⁺ 438.18.

Examples 77 to 86

Compounds listed in Table 8 were prepared using methods described inExample 74.

TABLE 8

HPLC ret. Time, min. Ex. (column No. G conditions)* [M + H]⁺ 77

3.13 452.22 78

3.36 466.24 79

3.63 480.26 80

2.64 509.23 81

2.72 523.26 82

3.37 508.21 83

3.20 482.23 84

2.72 535.56 85

3.06 512.47 86

3.31 496.51 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

Example 871-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-N-(piperidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxamide

1-(2-chloro-4-fluorophenyl)-5-(1H-indole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylicacid (Example 76, 40 mg) was coupled to tert-butyl4-aminopiperidine-1-carboxylate using the method described in Example74, Step G, to afford the Boc-protected intermediate as a white solidwhich was then dissolved in dioxane (1 mL), and 4 N anhyd.HCl in dioxane(1 mL) was added. After stirring at rt for 3 h, the solvent was removedunder vacuum and the residue was purified by reverse phase preparativeHPLC (HPLC conditions: YMC S5 20×100 mm, 10 min. run, solvent A: 10%MeOH, 90% H₂O, 0.1% TFA; solvent B: 90% MeOH, 10% H₂O, 0.1% TFA).Fractions containing the desired product were collected and concentratedto remove the methanol and the remaining aqueous portion was neutralizedby the addition of satd. aq. sodium bicarbonate. The resulting solid wascollected by vacuum filtration and dried under vacuum to afford thetitle compound 87 as a white solid (46 mg, 99%). HPLC Ret. Time=2.72 min(HPLC conditions: Ballistic YMC S5 ODS 4.6×50 mm column with a binarysolvent system where solvent A=10% methanol, 90% water, 0.2% phosphoricacid and solvent B=90% methanol, 10% water, and 0.2% phosphoric acid,flow rate=4 mL/min, linear gradient time=4 min, start % B=0, final %B=100). LCMS [M+H]⁺ 521.63.

Example 88(4-(2,4-difluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methoxyphenyl)methanone

Step A 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one

To a solution of sodium methoxide (1.67 g, 30.9 mmol) in anhydrous MeOH(10 mL) at room temperature was added formamidine acetate (1.15 g, 11mmol) in one portion as solid followed byethyl-1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (2.63 g,8.83 mmol) in one portion. The reaction mixture was stirred at rt for 20h. The reaction was cooled at 0° C., and water (6 mL) was added followedby acetic acid (0.63 mL, 11 mmol) and the mixture was stirred at rt for1 h. The mixture was concentrated under vacuum to remove the methanoland then stirred at rt overnight. The resulting solid was collected byfiltration and washed with water (5 mL×3) and dried on filter to affordthe title compound a (1.50 g, 70%) as an orange solid. LCMS [M+H]⁺242.16.

Step B 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (Step A,1.50 g, 6.22 mmol) in toluene (25 mL) were sequentially added DIPEA(0.87 mL, 5.0 mmol) and POCl₃ (0.70 mL, 7.46 mmol). The contents wereheated at 105° C. for 2 hour, cooled to rt, diluted with dichloromethane(100 mL) and stirred with cold aq. sat'd NaHCO₃ (150 mL) for 1 h. Thedichloromethane layer was dried over sodium sulfate and concentratedunder reduced pressure to afford the title compound b (1.61 g) as a darkoil. LCMS [M+H]⁺ 260.08.

Step C7-benzyl-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

To 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Step B,1.61 g, 6.22 mmol) in toluene (25 mL) were sequentially added2,4-difluorophenylboronic acid (1.18 g, 7.46 mmol), 2M aq potassiumcarbonate (6.2 mL, 12.4 mmol), ethanol (3.1 mL) andtetrakis(triphenylphosphine)palladium (0.36 g, 0.31 mmol) under an argonatmosphere. The contents were heated at 110° C. for 10 hour, cooled toroom temperature, concentrated under reduced pressure and partitionedbetween ethyl acetate (2×150 mL) and water (50 mL). The ethyl acetatelayer was extracted with aq. HCl (1N, 100 mL×3) and the aqueous portionwas cooled with ice bath and neutralized with aq. NaOH (10N) to pH ˜12,saturated with NaCl and extracted with dichloromethane (4×100 mL). Thedichloromethane layer was dried over sodium sulfate and concentratedunder reduced pressure to afford the title compound c (0.81 g, 38% twosteps) as a dark oil. LCMS [M+H]⁺ 338.11.

Step D 4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride

To7-benzyl-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(Step C, 0.81 g, 2.4 mmol) in dichloromethane (10 mL) at 0° C. was addedDIPEA (0.75 mL, 4.3 mmol) and 1-chloroethylchloroformate (0.34 mL, 3.1mmol). The contents were stirred at 0° C. for 1 hour and at roomtemperature for 20 hours. The reaction was stirred with cold aq. sat'dNaHCO³ (50 mL) for 1 hour and extracted with dichloromethane (2×100 mL).The dichloromethane layer was dried over sodium sulfate and concentratedunder reduced pressure dryness. The resulting intermediate was dissolvedin methanol (9 mL) and heated at reflux for 1 hour and concentratedunder reduced pressure to give dark oil, which was triturated with hotethyl acetate and recrystallized from dichloromethane and ethyl acetateto give the title compound d as a dark solid.

Step E(4-(2,4-difluorophenyl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)(2-methoxyphenyl)methanone

To a solution of4-(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride (Step D, 20 mg, 0.07 mmol) in anhydrous dichloromethane(0.3 mL) and diisopropylethylamine (37 μL, 0.21 mmol) were added2-methoxybenzoyl chloride, and the contents were stirred at rt for 15minutes. The reaction mixture was concentrated to remove the solvent andthe residue was subjected to reverse phase preparative HPLC (YMC S520×100 mm, 10 min. run, solvent A: 10% MeOH, 90% H₂O, 0.1% TFA; solventB: 90% MeOH, 10% H₂O, 0.1% TFA). The desired fractions were collected,concentrated under reduced pressure and lyophilized to yield thetrifluoroacetic acid salt of the title compound 88 (12 mgs) as a tansolid. HPLC Ret. Time=2.76 min (HPLC conditions: Ballistic YMC S5 ODS4.6×50 mm column with a binary solvent system where solvent A=10%methanol, 90% water, 0.2% phosphoric acid and solvent B=90% methanol,10% water, and 0.2% phosphoric acid, flow rate=4 mL/min, linear gradienttime=4 min, start % B=0, final % B=100). LCMS [M+H]⁺ 382.14.

Examples 89 to 96

Compounds listed in Table 9 were prepared using methods described inExample 88.

TABLE 9

HPLC ret. Time, min. Ex. (column No. G conditions)* [M + H]⁺ 89

2.81 352.12 90

2.95 366.17 91

2.81 370.15 92

2.86 370.14 93

2.92 386.07 94

2.76 388.11 95

2.79 412.13 96

2.83 538.32 *Ballistic YMC S5 ODS 4.6 × 50 mm column with a binarysolvent system where solvent A = 10% methanol, 90% water, 0.2%phosphoric acid and solvent B = 90% methanol, 10% water, and 0.2%phosphoric acid, flow rate = 4 mL/min, linear gradient time = 4 min,start % B = 0, final % B = 100.

1. A compound of Formula (I):

and enantiomers, diastereomers and pharmaceutically-acceptable saltsthereof, wherein: L and M are each independently selected from the groupconsisting of —N— and —C═; wherein both L and M cannot be —N— at thesame time; Q is selected from the group consisting of —N—, —C═, and abond, wherein: (a) Q is a bond when L is —N— and M is —C═; (b) Q is abond when L is —C═ and M is —N—; and (c) Q is —N═ or —C═ when L and Mare both —C═; R¹ and R² are each independently selected at eachoccurrence from the group consisting of hydroxyl, halo, haloalkyl,optionally substituted amino, optionally substituted alkoxy, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted heterocyclo, optionally substituted benzyl, optionallysubstituted benzoyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted carbamoyl and —[C(O)]₂NR⁷R⁸, whereineach of R⁷ and R⁸ is independently an optionally substituted C₁₋₆ alkyl,and further wherein R⁷ and R⁸ can be taken together with the atoms towhich they are attached to form an optionally substituted 5-6 memberring; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, hydroxyl, halo, haloalkyl, optionallysubstituted amino, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted heterocyclo, optionally substitutedbenzyl, optionally substituted benzoyl, optionally substituted aryl,optionally substituted heteroaryl; CO₂R¹¹ CONR¹¹R¹² and NR¹¹R¹², whereineach of R¹¹ and R¹² are independently selected from the group consistingof H, C1-C6 straight or branched chain alkyl, C1-C4 straight or branchedchain alkyl amino, C1-C4 straight or branched chain dialkyl amino, C1-C4straight or branched chain alkyl with an OH group, and C4-C10heterocyclo with 1-3 members selected from the group consisting of N, Sand O; provided there are no O—O or S—S bonds in R³ and R⁴ and any ofthe heterocyclo groups can be optionally substituted with a member ofthe group consisting of C1-C4 alkyl, optionally substituted amino, andalkyl amino; ring A is aryl or heteroaryl; B is —(CR⁵R⁶)_(q)— wherein R⁵and R⁶ are each independently selected from the group consisting ofhydrogen and optionally substituted alkyl; m is 0-2, wherein when m=2then (a) the 2 R¹ groups can be separate substituents or (b) the 2 R¹groups, together with the carbons to which they are attached can form afused ring, wherein (a) and (b) can each optionally be substituted witha member selected from the group consisting of cycloalkyl, benzyl,benzoyl, aryl, heterocyclo and heteroaryl; and n and q are eachindependently 0-3.
 2. A compound according to claim 1 wherein; R¹ isselected from the group consisting of hydrogen, halo, C1-C6 alkyl, cyanoand haloalkyl, wherein the haloalkyls have 1-3 carbons and 1-5 halogens;R² is selected from the group consisting of hydrogen; hydroxyl; halo;haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens;C1-C6 alkoxy; cyano; optionally substituted C1-C4 alkyl; C3-C6cycloalkyl; heterocyclo; aryl selected from phenyl and naphthyl;heteroaryl selected from pyridyl, thiophene, thiazole, indole, indazole,azaindole, quinoline, thiazole, benzthiazole, benzofuran andbenzimidazole; and —[C(O)]₂NR⁷R⁸, wherein each of R⁷ and R⁸ isindependently selected to be H or an optionally substituted C₁₋₆ alkyl,or R⁷ and R⁵ can be taken together with the carbons to which they areattached to form an optionally substituted 5-6 membered ring; R³ isselected from the group consisting of hydrogen and C1-C₃ alkyl; R⁴ isselected from the group consisting of hydrogen; hydroxyl, halo,haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens,CO₂R¹¹, CONR¹¹R¹² and NR¹¹R¹² wherein each of R¹¹ and R¹² areindependently selected from the group consisting of H, C1-C6 straight orbranched chain alkyl, C1-C4 straight or branched chain alkyl amino,C1-C4 straight or branched chain dialkyl amino, C1-C4 straight orbranched chain alkyl with an OH group; and C4-C10 heterocyclo with 1-3members selected from the group consisting of N, S and O, provided thereare no O—O or S—S bonds in R⁴ and the heterocyclo group can beoptionally substituted with a member selected from the group consistingof C1-C4 alkyl, optionally substituted amino, and alkyl amino; B is—(CR⁵R⁶)_(q)— wherein R⁵ and R⁶ are each independently selected from thegroup consisting of H and optionally substituted C1-C4 alkyl; ring A isa aryl or heteroaryl selected from the group consisting of phenyl,naphthyl, pyridyl, thiophene, indole, indazole, azaindole, quinoline,thiazole, benzthiazole, benzofuran and benzimidazole; m is 0-2; n is0-2; and q is 0-2.
 3. A compound according to claim 2 wherein q is
 0. 4.A compound according to claim 1 wherein Q is a bond when L is —N— and Mis —C═; ring A is selected from the group consisting of phenyl, indoleand pyrrolo[2, 3-b]pyridine; q is 0; m is 1 or 2; n is 1 or 3; R¹ isselected from the group consisting of halo, halo-C₁₋₃ alkyl andoptionally substituted C₁₋₃ alkyl; R² is selected from the groupconsisting of halo, halo-C₁₋₃ alkyl, optionally substituted C₁₋₃ alkyl,C₁₋₃ alkoxy and —[C(O)]₂NR⁷R⁸; and R³ and R⁴ are each hydrogen.
 5. Acompound according to claim 1 selected from the group consisting of:


6. A compound according to claim 1 wherein: Q is a bond when L is —C═and M is —N—; q is 0; R¹ is halo or C₁₋₃ alkyl; R² is selected from thegroup consisting of halo, halo-C₁₋₃ alkyl, optionally substituted C₁₋₃alkyl, optionally substituted C₁₋₃ alkoxy, and —[C(O)]₂NR⁷R⁸ R³ ishydrogen; R⁴ is hydrogen or —C(O)NR⁹R¹⁰ wherein —C(O)NR⁹R¹⁰; ring A isselected from the group consisting of phenyl, indole, indazole,benzo-imidazole, pyrrolo[2,3-b]pyridine and2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.
 7. A compound according toclaim 1 selected from the group consisting of:


8. A compound according to claim 1 wherein: Q is —N═ when L and M areboth —C═; ring A is an indole; m is 2; n is 3; q is 0; R¹ is halo; R² ishalo, C₁₋₃ alkyl or —[C(O)]₂NR⁷R⁸ wherein each of R⁷ and R⁸ isindependently a C₁₋₃ alkyl; and R³ and R⁴ are each hydrogen.
 9. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier or diluent.
 10. A method oftreating an inflammatory disorder comprising administering to a patientin need of such treatment a pharmaceutical composition according toclaim
 1. 11. The method of claim 12, wherein the inflammatory disorderis selected from the group consisting of asthma, adult respiratorydistress syndrome, chronic obstructive pulmonary disease, chronicpulmonary inflammatory disease, diabetes, inflammatory bowel disease,osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis,multiple myeloma, pain, myocardial ischemia and arthritis includingrheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubellaarthritis, gouty arthritis and osteoarthritis.
 12. A method ofinhibiting p38 kinase in a mammal comprising administering to the mammalin need of such treatment at least one compound according to claim 1.